96 results on '"Achim Lass"'
Search Results
2. Effect of astaxanthin in type-2 diabetes -induced APPxhQC transgenic and NTG mice
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Joshua Adekunle Babalola, Anika Stracke, Tina Loeffler, Irene Schilcher, Spyridon Sideromenos, Stefanie Flunkert, Joerg Neddens, Ake Lignell, Manuela Prokesch, Ute Pazenboeck, Herbert Strobl, Jelena Tadic, Gerd Leitinger, Achim Lass, Birgit Hutter-Paier, and Gerald Hoefler
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Alzheimer's disease ,Type 2 diabetes ,Pyroglutamylation ,Metabolic perturbation ,Astaxanthin ,Internal medicine ,RC31-1245 - Abstract
Objectives: Aggregation and misfolding of amyloid beta (Aβ) and tau proteins, suggested to arise from post-translational modification processes, are thought to be the main cause of Alzheimer's disease (AD). Additionally, a plethora of evidence exists that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia to the pathogenesis of AD. We thus investigated the combinatory effect of T2D and human glutaminyl cyclase activity (pyroglutamylation), on the pathology of AD and whether astaxanthin (ASX) treatment ameliorates accompanying pathophysiological manifestations. Methods: Male transgenic AD mice, APPxhQC, expressing human APP751 with the Swedish and the London mutation and human glutaminyl cyclase (hQC) enzyme and their non-transgenic (NTG) littermates were used. Both APPxhQC and NTG mice were allocated to 3 groups, control, T2D-control, and T2D-ASX. Mice were fed control or high fat diet ± ASX for 13 weeks starting at an age of 11–12 months. High fat diet fed mice were further treated with streptozocin for T2D induction. Effects of genotype, T2D induction, and ASX treatment were evaluated by analysing glycemic readouts, lipid concentration, Aβ deposition, hippocampus-dependent cognitive function and nutrient sensing using immunosorbent assay, ELISA-based assays, western blotting, immunofluorescence staining, and behavioral testing via Morris water maze (MWM), respectively. Results: APPxhQC mice presented a higher glucose sensitivity compared to NTG mice. T2D-induced brain dysfunction was more severe in NTG compared to the APPxhQC mice. T2D induction impaired memory functions while increasing hepatic LC3B, ABCA1, and p65 levels in NTG mice. T2D induction resulted in a progressive shift of Aβ from the soluble to insoluble form in APPxhQC mice. ASX treatment reversed T2D-induced memory dysfunction in NTG mice and in parallel increased hepatic pAKT while decreasing p65 and increasing cerebral p-S6rp and p65 levels. ASX treatment reduced soluble Aβ38 and Aβ40 and insoluble Aβ40 levels in T2D-induced APPxhQC mice. Conclusions: We demonstrate that T2D induction in APPxhQC mice poses additional risk for AD pathology as seen by increased Aβ deposition. Although ASX treatment reduced Aβ expression in T2D-induced APPxhQC mice and rescued T2D-induced memory impairment in NTG mice, ASX treatment alone may not be effective in cases of T2D comorbidity and AD.
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- 2024
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3. Acute retinol mobilization by retinol-binding protein 4 in mouse liver induces fibroblast growth factor 21 expression
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Julia S. Steinhoff, Carina Wagner, Ulrike Taschler, Sascha Wulff, Marie F. Kiefer, Konstantin M. Petricek, Sylvia J. Wowro, Moritz Oster, Roberto E. Flores, Na Yang, Chen Li, Yueming Meng, Manuela Sommerfeld, Stefan Weger, Andrea Henze, Jens Raila, Achim Lass, and Michael Schupp
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vitamin A ,retinoids ,glucose ,hepatic retinol mobilization ,retinyl ester storage ,obesity ,Biochemistry ,QD415-436 - Abstract
Hepatocytes secrete retinol-binding protein 4 (RBP4) into circulation, thereby mobilizing vitamin A from the liver to provide retinol for extrahepatic tissues. Obesity and insulin resistance are associated with elevated RBP4 levels in the blood. However, in a previous study, we observed that chronically increased RBP4 by forced Rbp4 expression in the liver does not impair glucose homeostasis in mice. Here, we investigated the effects of an acute mobilization of hepatic vitamin A stores by hepatic overexpression of RBP4 in mice. We show that hepatic retinol mobilization decreases body fat content and enhances fat turnover. Mechanistically, we found that acute retinol mobilization increases hepatic expression and serum levels of fibroblast growth factor 21 (FGF21), which is regulated by retinol mobilization and retinoic acid in primary hepatocytes. Moreover, we provide evidence that the insulin-sensitizing effect of FGF21 is associated with organ-specific adaptations in retinoid homeostasis. Taken together, our findings identify a novel crosstalk between retinoid homeostasis and FGF21 in mice with acute RBP4-mediated retinol mobilization from the liver.
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- 2022
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4. Advanced lipodystrophy reverses fatty liver in mice lacking adipocyte hormone-sensitive lipase
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Laura Pajed, Ulrike Taschler, Anna Tilp, Peter Hofer, Petra Kotzbeck, Stephanie Kolleritsch, Franz P. W. Radner, Isabella Pototschnig, Carina Wagner, Margarita Schratter, Sandra Eder, Sabrina Huetter, Renate Schreiber, Guenter Haemmerle, Thomas O. Eichmann, Martina Schweiger, Gerald Hoefler, Erin E. Kershaw, Achim Lass, and Gabriele Schoiswohl
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Biology (General) ,QH301-705.5 - Abstract
Pajed et al. investigate the role of adipocyte hormone-sensitive lipase (HSL) in whole body energy homeostasis. They show that adipocyte-specific HSL Knockout (AHKO) mice fed high fat diet develop fatty liver. Interestingly, this phenotype reverses in aged AHKO mice, possibly due to blunted lipolytic activity in adipose tissue with pronounced lipodystrophy.
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- 2021
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5. KIAA1363 affects retinyl ester turnover in cultured murine and human hepatic stellate cells
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Carina Wagner, Victoria Hois, Annalena Eggeling, Lisa-Maria Pusch, Laura Pajed, Patrick Starlinger, Thierry Claudel, Michael Trauner, Robert Zimmermann, Ulrike Taschler, and Achim Lass
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KIAA1363 ,retinyl ester hydrolase ,vitamin A ,retinol ,hepatic stellate cells ,liver ,Biochemistry ,QD415-436 - Abstract
Large quantities of vitamin A are stored as retinyl esters (REs) in specialized liver cells, the hepatic stellate cells (HSCs). To date, the enzymes controlling RE degradation in HSCs are poorly understood. In this study, we identified KIAA1363 (also annotated as arylacetamide deacetylase 1 or neutral cholesterol ester hydrolase 1) as a novel RE hydrolase. We show that KIAA1363 is expressed in the liver, mainly in HSCs, and exhibits RE hydrolase activity at neutral pH. Accordingly, addition of the KIAA1363-specific inhibitor JW480 largely reduced RE hydrolase activity in lysates of cultured murine and human HSCs. Furthermore, cell fractionation experiments and confocal microscopy studies showed that KIAA1363 localizes to the endoplasmic reticulum. We demonstrate that overexpression of KIAA1363 in cells led to lower cellular RE content after a retinol loading period. Conversely, pharmacological inhibition or shRNA-mediated silencing of KIAA1363 expression in cultured murine and human HSCs attenuated RE degradation. Together, our data suggest that KIAA1363 affects vitamin A metabolism of HSCs by hydrolyzing REs at the endoplasmic reticulum, thereby counteracting retinol esterification and RE storage in lipid droplets.
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- 2022
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6. Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice
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Gernot F. Grabner, Nermeen Fawzy, Renate Schreiber, Lisa M. Pusch, Dominik Bulfon, Harald Koefeler, Thomas O. Eichmann, Achim Lass, Martina Schweiger, Gunther Marsche, Gabriele Schoiswohl, Ulrike Taschler, and Robert Zimmermann
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lipid metabolism ,phospholipids ,liver ,pancreas ,adipose tissue ,nutritional state ,Biochemistry ,QD415-436 - Abstract
Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid, is a phospholipid that promotes lipid sorting in late endosomes/lysosomes by activating lipid hydrolases and lipid transfer proteins. Changes in the cellular BMP content therefore reflect an altered metabolic activity of the endolysosomal system. Surprisingly, little is known about the physiological regulation of BMP. In this study, we investigated the effects of nutritional and metabolic factors on BMP profiles of whole tissues and parenchymal and nonparenchymal cells. Tissue samples were obtained from fed, fasted, 2 h refed, and insulin-treated mice, as well as from mice housed at 5°C, 22°C, or 30°C. These tissues exhibited distinct BMP profiles that were regulated by the nutritional state in a tissue-specific manner. Insulin treatment was not sufficient to mimic refeeding-induced changes in tissue BMP levels, indicating that BMP metabolism is regulated by other hormonal or nutritional factors. Tissue fractionation experiments revealed that fasting drastically elevates BMP levels in hepatocytes and pancreatic cells. Furthermore, we observed that the BMP content in brown adipose tissue strongly depends on housing temperatures. In conclusion, our observations suggest that BMP concentrations adapt to the metabolic state in a tissue- and cell-type-specific manner in mice. Drastic changes observed in hepatocytes, pancreatic cells, and brown adipocytes suggest that BMP plays a role in the functional adaption to nutrient starvation and ambient temperature.
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- 2020
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7. Comparative transcriptomics reveals candidate carotenoid color genes in an East African cichlid fish
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Ehsan Pashay Ahi, Laurène A. Lecaudey, Angelika Ziegelbecker, Oliver Steiner, Ronald Glabonjat, Walter Goessler, Victoria Hois, Carina Wagner, Achim Lass, and Kristina M. Sefc
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Carotenoids ,Body coloration ,Color genes ,Gene expression ,Cichlidae ,Tropheus ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Carotenoids contribute significantly to animal body coloration, including the spectacular color pattern diversity among fishes. Fish, as other animals, derive carotenoids from their diet. Following uptake, transport and metabolic conversion, carotenoids allocated to body coloration are deposited in the chromatophore cells of the integument. The genes involved in these processes are largely unknown. Using RNA-Sequencing, we tested for differential gene expression between carotenoid-colored and white skin regions of a cichlid fish, Tropheus duboisi “Maswa”, to identify genes associated with carotenoid-based integumentary coloration. To control for positional gene expression differences that were independent of the presence/absence of carotenoid coloration, we conducted the same analyses in a closely related population, in which both body regions are white. Results A larger number of genes (n = 50) showed higher expression in the yellow compared to the white skin tissue than vice versa (n = 9). Of particular interest was the elevated expression level of bco2a in the white skin samples, as the enzyme encoded by this gene catalyzes the cleavage of carotenoids into colorless derivatives. The set of genes with higher expression levels in the yellow region included genes involved in xanthophore formation (e.g., pax7 and sox10), intracellular pigment mobilization (e.g., tubb, vim, kif5b), as well as uptake (e.g., scarb1) and storage (e.g., plin6) of carotenoids, and metabolic conversion of lipids and retinoids (e.g., dgat2, pnpla2, akr1b1, dhrs). Triglyceride concentrations were similar in the yellow and white skin regions. Extracts of integumentary carotenoids contained zeaxanthin, lutein and beta-cryptoxanthin as well as unidentified carotenoid structures. Conclusion Our results suggest a role of carotenoid cleavage by Bco2 in fish integumentary coloration, analogous to previous findings in birds. The elevated expression of genes in carotenoid-rich skin regions with functions in retinol and lipid metabolism supports hypotheses concerning analogies and shared mechanisms between these metabolic pathways. Overlaps in the sets of differentially expressed genes (including dgat2, bscl2, faxdc2 and retsatl) between the present study and previous, comparable studies in other fish species provide useful hints to potential carotenoid color candidate genes.
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- 2020
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8. ABHD5—A Regulator of Lipid Metabolism Essential for Diverse Cellular Functions
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Margarita Schratter, Achim Lass, and Franz P. W. Radner
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ABHD5 ,CGI-58 ,ATGL ,PNPLA3 ,triglyceride ,lipid metabolism ,Microbiology ,QR1-502 - Abstract
The α/β-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.
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- 2022
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9. Metabolic disease and ABHD6 alter the circulating bis(monoacylglycerol)phosphate profile in mice and humans
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Gernot F. Grabner, Nermeen Fawzy, Maria A. Pribasnig, Markus Trieb, Ulrike Taschler, Michael Holzer, Martina Schweiger, Heimo Wolinski, Dagmar Kolb, Angela Horvath, Rolf Breinbauer, Thomas Rülicke, Roland Rabl, Achim Lass, Vanessa Stadlbauer, Birgit Hutter-Paier, Rudolf E. Stauber, Peter Fickert, Rudolf Zechner, Gunther Marsche, Thomas O. Eichmann, and Robert Zimmermann
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nonalcoholic fatty liver disease ,obesity ,lysosomal storage disorders ,phospholipids ,lysobisphosphatidic acid ,α/β-hydrolase domain-containing 6 ,Biochemistry ,QD415-436 - Abstract
Bis(monoacylglycerol)phosphate (BMP) is a phospholipid that is crucial for lipid degradation and sorting in acidic organelles. Genetic and drug-induced lysosomal storage disorders (LSDs) are associated with increased BMP concentrations in tissues and in the circulation. Data on BMP in disorders other than LSDs, however, are scarce, and key enzymes regulating BMP metabolism remain elusive. Here, we demonstrate that common metabolic disorders and the intracellular BMP hydrolase α/β-hydrolase domain-containing 6 (ABHD6) affect BMP metabolism in mice and humans. In mice, dietary lipid overload strongly affects BMP concentration and FA composition in the liver and plasma, similar to what has been observed in LSDs. Notably, distinct changes in the BMP FA profile enable a clear distinction between lipid overload and drug-induced LSDs. Global deletion of ABHD6 increases circulating BMP concentrations but does not cause LSDs. In humans, nonalcoholic fatty liver disease and liver cirrhosis affect the serum BMP FA composition and concentration. Furthermore, we identified a patient with a loss-of-function mutation in the ABHD6 gene, leading to an altered circulating BMP profile. In conclusion, our results suggest that common metabolic diseases and ABHD6 affect BMP metabolism in mice and humans.
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- 2019
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10. KIAA1363—A Multifunctional Enzyme in Xenobiotic Detoxification and Lipid Ester Hydrolysis
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Carina Wagner, Victoria Hois, Ulrike Taschler, Michael Schupp, and Achim Lass
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KIAA1363 ,neutral cholesterol ester hydrolase 1 ,arylacetamide deacetylase-like 1 ,lipid metabolism ,xenobiotics ,Microbiology ,QR1-502 - Abstract
KIAA1363, annotated as neutral cholesterol ester hydrolase 1 (NCEH1), is a member of the arylacetamide deacetylase (AADAC) protein family. The name-giving enzyme, AADAC, is known to hydrolyze amide and ester bonds of a number of xenobiotic substances, as well as clinical drugs and of endogenous lipid substrates such as diglycerides, respectively. Similarly, KIAA1363, annotated as the first AADAC-like protein, exhibits enzymatic activities for a diverse substrate range including the xenobiotic insecticide chlorpyrifos oxon and endogenous substrates, acetyl monoalkylglycerol ether, cholesterol ester, and retinyl ester. Two independent knockout mouse models have been generated and characterized. However, apart from reduced acetyl monoalkylglycerol ether and cholesterol ester hydrolase activity in specific tissues and cell types, no gross-phenotype has been reported. This raises the question of its physiological role and whether it functions as drug detoxifying enzyme and/or as hydrolase/lipase of endogenous substrates. This review delineates the current knowledge about the structure, function and of the physiological role of KIAA1363, as evident from the phenotypical changes inflicted by pharmacological inhibition or by silencing as well as knockout of KIAA1363 gene expression in cells, as well as mouse models, respectively.
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- 2022
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11. ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier[S]
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Benedikt Kien, Susanne Grond, Guenter Haemmerle, Achim Lass, Thomas O. Eichmann, and Franz P.W. Radner
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α/β-hydrolase domain-containing 5 ,patatin-like phospholipase domain-containing 1 ,ceramides ,disease ,epidermis ,fatty acid ,Biochemistry ,QD415-436 - Abstract
Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and α/β-hydrolase domain-containing 5 (ABHD5), also known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Individuals with mutations in either of these genes show a defect in epidermal ω-O-acylceramide (AcylCer) biosynthesis, suggesting that PNPLA1 and ABHD5 act in the same metabolic pathway. In this report, we identified ABHD5 as a coactivator of PNPLA1 that stimulates the esterification of ω-hydroxy ceramides with linoleic acid for AcylCer biosynthesis. ABHD5 interacts with PNPLA1 and recruits the enzyme to its putative triacylglycerol substrate onto cytosolic lipid droplets. Conversely, alleles of ABHD5 carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis. Our findings establish an important biochemical function of ABHD5 in interacting with PNPLA1 to synthesize crucial epidermal lipids, emphasizing the significance of these proteins in the formation of a functional skin permeability barrier.
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- 2018
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12. Biological Functions of RBP4 and Its Relevance for Human Diseases
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Julia S. Steinhoff, Achim Lass, and Michael Schupp
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RBP4 ,retinol transport ,liver ,retinoids ,vitamin A ,lipocalin ,Physiology ,QP1-981 - Abstract
Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body’s vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4’s actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.
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- 2021
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13. Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease
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Julia S. Steinhoff, Achim Lass, and Michael Schupp
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RBP4 ,vitamin A ,retinoids ,retinol transport ,retinoid homeostasis ,metabolism ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations.
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- 2022
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14. A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics
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Kirsten Tschapalda, Ya-Qin Zhang, Li Liu, Kseniya Golovnina, Thomas Schlemper, Thomas O. Eichmann, Madhu Lal-Nag, Urmila Sreenivasan, John McLenithan, Slava Ziegler, Carole Sztalryd, Achim Lass, Douglas Auld, Brian Oliver, Herbert Waldmann, Zhuyin Li, Min Shen, Matthew B. Boxer, and Mathias Beller
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Medicine ,Medicine (General) ,R5-920 - Abstract
Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened >320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.
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- 2016
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15. A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria
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Sandro Roier, Franz G. Zingl, Fatih Cakar, Sanel Durakovic, Paul Kohl, Thomas O. Eichmann, Lisa Klug, Bernhard Gadermaier, Katharina Weinzerl, Ruth Prassl, Achim Lass, Günther Daum, Joachim Reidl, Mario F. Feldman, and Stefan Schild
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Science - Abstract
Bacteria release outer membrane vesicles (OMVs) that play important roles in pathogenesis and intercellular interactions. Here, Roier et al. provide evidence supporting that phospholipid accumulation in the outer leaflet of the outer membrane participates in OMV formation in Gram-negative bacteria.
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- 2016
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16. ATGL and CGI-58 are lipid droplet proteins of the hepatic stellate cell line HSC-T6
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Thomas O. Eichmann, Lukas Grumet, Ulrike Taschler, Jürgen Hartler, Christoph Heier, Aaron Woblistin, Laura Pajed, Manfred Kollroser, Gerald Rechberger, Gerhard G. Thallinger, Rudolf Zechner, Günter Haemmerle, Robert Zimmermann, and Achim Lass
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proteome ,lipidome ,neutral lipid hydrolase ,adipose triglyceride lipase ,Biochemistry ,QD415-436 - Abstract
Lipid droplets (LDs) of hepatic stellate cells (HSCs) contain large amounts of vitamin A [in the form of retinyl esters (REs)] as well as other neutral lipids such as TGs. During times of insufficient vitamin A availability, RE stores are mobilized to ensure a constant supply to the body. To date, little is known about the enzymes responsible for the hydrolysis of neutral lipid esters, in particular of REs, in HSCs. In this study, we aimed to identify LD-associated neutral lipid hydrolases by a proteomic approach using the rat stellate cell line HSC-T6. First, we loaded cells with retinol and FAs to promote lipid synthesis and deposition within LDs. Then, LDs were isolated and lipid composition and the LD proteome were analyzed. Among other proteins, we found perilipin 2, adipose TG lipase (ATGL), and comparative gene identification-58 (CGI-58), known and established LD proteins. Bioinformatic search of the LD proteome for α/β-hydrolase fold-containing proteins revealed no yet uncharacterized neutral lipid hydrolases. In in vitro activity assays, we show that rat (r)ATGL, coactivated by rat (r)CGI-58, efficiently hydrolyzes TGs and REs. These findings suggest that rATGL and rCGI-58 are LD-resident proteins in HSCs and participate in the mobilization of both REs and TGs.
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- 2015
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17. Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis
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Manoja K. Brahma, Rene C. Adam, Nina M. Pollak, Doris Jaeger, Kathrin A. Zierler, Nadja Pöcher, Renate Schreiber, Matthias Romauch, Tarek Moustafa, Sandra Eder, Thomas Ruelicke, Karina Preiss-Landl, Achim Lass, Rudolf Zechner, and Guenter Haemmerle
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adipose triglyceride lipase ,cardiac lipid and energy metabolism ,ER stress ,Biochemistry ,QD415-436 - Abstract
Fibroblast growth factor 21 (FGF21) is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPARα-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism. Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis.
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- 2014
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18. Cardiac-specific overexpression of perilipin 5 provokes severe cardiac steatosis via the formation of a lipolytic barrier[S]
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Nina M. Pollak, Martina Schweiger, Doris Jaeger, Dagmar Kolb, Manju Kumari, Renate Schreiber, Stephanie Kolleritsch, Philipp Markolin, Gernot F. Grabner, Christoph Heier, Kathrin A. Zierler, Thomas Rülicke, Robert Zimmermann, Achim Lass, Rudolf Zechner, and Guenter Haemmerle
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adipose triglyceride lipase ,cardiac lipid ,energy metabolism ,Biochemistry ,QD415-436 - Abstract
Cardiac triacylglycerol (TG) catabolism critically depends on the TG hydrolytic activity of adipose triglyceride lipase (ATGL). Perilipin 5 (Plin5) is expressed in cardiac muscle (CM) and has been shown to interact with ATGL and its coactivator comparative gene identification-58 (CGI-58). Furthermore, ectopic Plin5 expression increases cellular TG content and Plin5-deficient mice exhibit reduced cardiac TG levels. In this study we show that mice with cardiac muscle-specific overexpression of perilipin 5 (CM-Plin5) massively accumulate TG in CM, which is accompanied by moderately reduced fatty acid (FA) oxidizing gene expression levels. Cardiac lipid droplet (LD) preparations from CM of CM-Plin5 mice showed reduced ATGL- and hormone-sensitive lipase-mediated TG mobilization implying that Plin5 overexpression restricts cardiac lipolysis via the formation of a lipolytic barrier. To test this hypothesis, we analyzed TG hydrolytic activities in preparations of Plin5-, ATGL-, and CGI-58-transfected cells. In vitro ATGL-mediated TG hydrolysis of an artificial micellar TG substrate was not inhibited by the presence of Plin5, whereas Plin5-coated LDs were resistant toward ATGL-mediated TG catabolism. These findings strongly suggest that Plin5 functions as a lipolytic barrier to protect the cardiac TG pool from uncontrolled TG mobilization and the excessive release of free FAs.
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- 2013
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19. G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase
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Martina Schweiger, Margret Paar, Christina Eder, Janina Brandis, Elena Moser, Gregor Gorkiewicz, Susanne Grond, Franz P.W. Radner, Ines Cerk, Irina Cornaciu, Monika Oberer, Sander Kersten, Rudolf Zechner, Robert Zimmermann, and Achim Lass
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comparative gene identification-58 ,human lipolysis ,regulation ,insulin resistance ,Biochemistry ,QD415-436 - Abstract
The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel. Murine lipolysis largely depends on the activity of adipose triglyceride lipase (ATGL), which is regulated by two proteins annotated as comparative gene identification-58 (CGI-58) and G0/G1 switch gene-2 (G0S2). CGI-58 activates and G0S2 inhibits ATGL activity. In contrast to mice, the functional role of G0S2 in human adipocyte lipolysis is poorly characterized. Here we show that overexpression or silencing of G0S2 in human SGBS adipocytes decreases and increases lipolysis, respectively. Human G0S2 is upregulated during adipocyte differentiation and inhibits ATGL activity in a dose-dependent manner. Interestingly, C-terminally truncated ATGL mutants, which fail to localize to lipid droplets, translocate to the lipid droplet upon coexpression with G0S2, suggesting that G0S2 anchors ATGL to lipid droplets independent of ATGL's C-terminal lipid binding domain. Taken together, our results indicate that G0S2 also regulates human lipolysis by affecting enzyme activity and intracellular localization of ATGL. Increased lipolysis is known to contribute to the pathogenesis of insulin resistance, and G0S2 expression has been shown to be reduced in poorly controlled type 2 diabetic patients. Our data indicate that downregulation of G0S2 in adipose tissue could represent one of the underlying causes leading to increased lipolysis in the insulin-resistant state.
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- 2012
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20. Lipidomic analysis of lipid droplets from murine hepatocytes reveals distinct signatures for nutritional stress
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Chandramohan Chitraju, Martin Trötzmüller, Jürgen Hartler, Heimo Wolinski, Gerhard G. Thallinger, Achim Lass, Rudolf Zechner, Robert Zimmermann, Harald C. Köfeler, and Friedrich Spener
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lipidomics ,mass spectrometry ,high-fat diet ,fasting ,steatosis ,principal component analysis ,Biochemistry ,QD415-436 - Abstract
Liver steatosis can be induced by fasting or high-fat diet. We investigated by lipidomic analysis whether such metabolic states are reflected in the lipidome of hepatocyte lipid droplets (LDs) from mice fed normal chow diet (FED), fasted (FAS), or fed a high-fat diet (HFD). LC-MS/MS at levels of lipid species profiles and of lipid molecular species uncovered a FAS phenotype of LD enriched in triacylglycerol (TG) molecular species with very long-chain (VLC)-PUFA residues and an HFD phenotype with less unsaturated TG species in addition to characteristic lipid marker species. Nutritional stress did not result in dramatic structural alterations in diacylglycerol (DG) and phospholipid (PL) classes. Moreover, molecular species of bulk TG and of DG indicated concomitant de novo TG synthesis and lipase-catalyzed degradation to be active in LDs. DG species with VLC-PUFA residues would be preferred precursors for phosphatidylcholine (PC) species, the others for TG molecular species. In addition, molecular species of PL classes fitted the hepatocyte Kennedy and phosphatidylethanolamine methyltransferase pathways. We demonstrate that lipidomic analysis of LDs enables phenotyping of nutritional stress. TG species are best suited for such phenotyping, whereas structural analysis of TG, DG, and PL molecular species provides metabolic insights.
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- 2012
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21. Cholesteryl ester hydrolase activity is abolished in HSL macrophages but unchanged in macrophages lacking KIAA1363[S]
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Marlene Buchebner, Thomas Pfeifer, Nora Rathke, Prakash G. Chandak, Achim Lass, Renate Schreiber, Adelheid Kratzer, Robert Zimmermann, Wolfgang Sattler, Harald Koefeler, Eleonore Fröhlich, Gerhard M. Kostner, Ruth Birner-Gruenberger, Kyle P. Chiang, Guenter Haemmerle, Rudolf Zechner, Sanja Levak-Frank, Benjamin Cravatt, and Dagmar Kratky
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2-acetyl monoalkylglycerol ether hydrolase ,cholesterol metabolism ,lipase ,lipids ,triacylglycerol ,Biochemistry ,QD415-436 - Abstract
Cholesteryl ester (CE) accumulation in macrophages represents a crucial event during foam cell formation, a hallmark of atherogenesis. Here we investigated the role of two previously described CE hydrolases, hormone-sensitive lipase (HSL) and KIAA1363, in macrophage CE hydrolysis. HSL and KIAA1363 exhibited marked differences in their abilities to hydrolyze CE, triacylglycerol (TG), diacylglycerol (DG), and 2-acetyl monoalkylglycerol ether (AcMAGE), a precursor for biosynthesis of platelet-activating factor (PAF). HSL efficiently cleaved all four substrates, whereas KIAA1363 hydrolyzed only AcMAGE. This contradicts previous studies suggesting that KIAA1363 is a neutral CE hydrolase. Macrophages of KIAA1363−/− and wild-type mice exhibited identical neutral CE hydrolase activity, which was almost abolished in tissues and macrophages of HSL−/− mice. Conversely, AcMAGE hydrolase activity was diminished in macrophages and some tissues of KIAA1363−/− but unchanged in HSL−/− mice. CE turnover was unaffected in macrophages lacking KIAA1363 and HSL, whereas cAMP-dependent cholesterol efflux was influenced by HSL but not by KIAA1363. Despite decreased CE hydrolase activities, HSL−/− macrophages exhibited CE accumulation similar to wild-type (WT) macrophages. We conclude that additional enzymes must exist that cooperate with HSL to regulate CE levels in macrophages. KIAA1363 affects AcMAGE hydrolase activity but is of minor importance as a direct CE hydrolase in macrophages.
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- 2010
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22. Adipose triglyceride lipase plays a key role in the supply of the working muscle with fatty acids
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Gabriele Schoiswohl, Martina Schweiger, Renate Schreiber, Gregor Gorkiewicz, Karina Preiss-Landl, Ulrike Taschler, Kathrin A. Zierler, Franz P.W. Radner, Thomas O. Eichmann, Petra C. Kienesberger, Sandra Eder, Achim Lass, Guenter Haemmerle, Thomas J. Alsted, Bente Kiens, Gerald Hoefler, Rudolf Zechner, and Robert Zimmermann
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exercise ,metabolism ,lipids ,glycogen ,Biochemistry ,QD415-436 - Abstract
FAs are mobilized from triglyceride (TG) stores during exercise to supply the working muscle with energy. Mice deficient for adipose triglyceride lipase (ATGL-ko) exhibit defective lipolysis and accumulate TG in adipose tissue and muscle, suggesting that ATGL deficiency affects energy availability and substrate utilization in working muscle. In this study, we investigated the effect of moderate treadmill exercise on blood energy metabolites and liver glycogen stores in mice lacking ATGL. Because ATGL-ko mice exhibit massive accumulation of TG in the heart and cardiomyopathy, we also investigated a mouse model lacking ATGL in all tissues except cardiac muscle (ATGL-ko/CM). In contrast to ATGL-ko mice, these mice did not accumulate TG in the heart and had normal life expectancy. Exercise experiments revealed that ATGL-ko and ATGL-ko/CM mice are unable to increase circulating FA levels during exercise. The reduced availability of FA for energy conversion led to rapid depletion of liver glycogen stores and hypoglycemia. Together, our studies suggest that ATGL-ko mice cannot adjust circulating FA levels to the increased energy requirements of the working muscle, resulting in an increased use of carbohydrates for energy conversion. Thus, ATGL activity is required for proper energy supply of the skeletal muscle during exercise.
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- 2010
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23. Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver
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Renate Schreiber, Ulrike Taschler, Heimo Wolinski, Andrea Seper, Stefanie N. Tamegger, Maria Graf, Sepp D. Kohlwein, Guenter Haemmerle, Robert Zimmermann, Rudolf Zechner, and Achim Lass
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vitamin A ,retinol ,retinyl ester hydrolase ,endoplasmic reticulum ,Biochemistry ,QD415-436 - Abstract
Excess dietary vitamin A is esterified with fatty acids and stored in the form of retinyl ester (RE) predominantly in the liver. According to the requirements of the body, liver RE stores are hydrolyzed and retinol is delivered to peripheral tissues. The controlled mobilization of retinol ensures a constant supply of the body with the vitamin. Currently, the enzymes catalyzing liver RE hydrolysis are unknown. In this study, we identified mouse esterase 22 (Es22) as potent RE hydrolase highly expressed in the liver, particularly in hepatocytes. The enzyme is located exclusively at the endoplasmic reticulum (ER), implying that it is not involved in the mobilization of RE present in cytosolic lipid droplets. Nevertheless, cell culture experiments revealed that overexpression of Es22 attenuated the formation of cellular RE stores, presumably by counteracting retinol esterification at the ER. Es22 was previously shown to form a complex with β-glucuronidase (Gus). Our studies revealed that Gus colocalizes with Es22 at the ER but does not affect its RE hydrolase activity. Interestingly, however, Gus was capable of hydrolyzing the naturally occurring vitamin A metabolite retinoyl β-glucuronide. In conclusion, our observations implicate that both Es22 and Gus play a role in liver retinoid metabolism.
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- 2009
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24. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores
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Rudolf Zechner, Petra C. Kienesberger, Guenter Haemmerle, Robert Zimmermann, and Achim Lass
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lipolysis ,hydrolase ,neutral lipid storage disease ,Biochemistry ,QD415-436 - Abstract
Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL- and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzyme's activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the “lipolysome,” a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL.
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- 2009
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25. Hepatic Retinyl Ester Hydrolases and the Mobilization of Retinyl Ester Stores
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Lukas Grumet, Ulrike Taschler, and Achim Lass
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retinyl ester hydrolase ,liver ,hepatocyte ,hepatic stellate cells ,lipid droplet ,mobilization ,Nutrition. Foods and food supply ,TX341-641 - Abstract
For mammals, vitamin A (retinol and metabolites) is an essential micronutrient that is required for the maintenance of life. Mammals cannot synthesize vitamin A but have to obtain it from their diet. Resorbed dietary vitamin A is stored in large quantities in the form of retinyl esters (REs) in cytosolic lipid droplets of cells to ensure a constant supply of the body. The largest quantities of REs are stored in the liver, comprising around 80% of the body’s total vitamin A content. These hepatic vitamin A stores are known to be mobilized under times of insufficient dietary vitamin A intake but also under pathological conditions such as chronic alcohol consumption and different forms of liver diseases. The mobilization of REs requires the activity of RE hydrolases. It is astounding that despite their physiological significance little is known about their identities as well as about factors or stimuli which lead to their activation and consequently to the mobilization of hepatic RE stores. In this review, we focus on the recent advances for the understanding of hepatic RE hydrolases and discuss pathological conditions which lead to the mobilization of hepatic RE stores.
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- 2016
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26. The minimal domain of adipose triglyceride lipase (ATGL) ranges until leucine 254 and can be activated and inhibited by CGI-58 and G0S2, respectively.
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Irina Cornaciu, Andras Boeszoermenyi, Hanna Lindermuth, Harald M Nagy, Ines K Cerk, Catharina Ebner, Barbara Salzburger, Astrid Gruber, Martina Schweiger, Rudolf Zechner, Achim Lass, Robert Zimmermann, and Monika Oberer
- Subjects
Medicine ,Science - Abstract
Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis. ATGL specifically hydrolyzes triacylglycerols (TGs), thereby generating diacylglycerols and free fatty acids. ATGL's enzymatic activity is co-activated by the protein comparative gene identification-58 (CGI-58) and inhibited by the protein G0/G1 switch gene 2 (G0S2). The enzyme is predicted to act through a catalytic dyad (Ser47, Asp166) located within the conserved patatin domain (Ile10-Leu178). Yet, neither an experimentally determined 3D structure nor a model of ATGL is currently available, which would help to understand how CGI-58 and G0S2 modulate ATGL's activity. In this study we determined the minimal active domain of ATGL. This minimal fragment of ATGL could still be activated and inhibited by CGI-58 and G0S2, respectively. Furthermore, we show that this minimal domain is sufficient for protein-protein interaction of ATGL with its regulatory proteins. Based on these data, we generated a 3D homology model for the minimal domain. It strengthens our experimental finding that amino acids between Leu178 and Leu254 are essential for the formation of a stable protein domain related to the patatin fold. Our data provide insights into the structure-function relationship of ATGL and indicate higher structural similarities in the N-terminal halves of mammalian patatin-like phospholipase domain containing proteins, (PNPLA1, -2,- 3 and -5) than originally anticipated.
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- 2011
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27. Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions
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Petra C. Kienesberger, Monika Oberer, Achim Lass, and Rudolf Zechner
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PNPLA ,ATGL ,adiponutrin ,GS2 ,GS2-like ,NTE ,Biochemistry ,QD415-436 - Abstract
The human genome expresses nine patatin-like phospholipase domain containing proteins (PNPLA1–9). Members of this family share a protein domain discovered initially in patatin, the most abundant protein of the potato tuber. Patatin is a lipid hydrolase with an unusual folding topology that differs from classical lipases. Mammalian PNPLAs include lipid hydrolases with specificities for diverse substrates such as triacylglycerols, phospholipids, and retinol esters. Analysis of induced mutant mouse models and the clinical phenotype of patients with mutations revealed important insights into the physiological role of several members of the PNPLA family. This review aims to summarize current knowledge of PNPLA proteins and to document their emerging importance in lipid and energy homeostasis.
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- 2009
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28. Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes
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Gernot F. Grabner, Nikolaus Guttenberger, Nicole Mayer, Anna K. Migglautsch-Sulzer, Christian Lembacher-Fadum, Nermeen Fawzy, Dominik Bulfon, Peter Hofer, Thomas Züllig, Lennart Hartig, Natalia Kulminskaya, Gabriel Chalhoub, Margarita Schratter, Franz P. W. Radner, Karina Preiss-Landl, Sarah Masser, Achim Lass, Rudolf Zechner, Karl Gruber, Monika Oberer, Rolf Breinbauer, and Robert Zimmermann
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Mice ,Colloid and Surface Chemistry ,Lipolysis ,Fatty Acids ,Adipocytes ,Animals ,Humans ,General Chemistry ,Biochemistry ,Catalysis ,Acyltransferases - Abstract
Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme-inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.
- Published
- 2022
29. Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease
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Michael Schupp, Achim Lass, and Julia S. Steinhoff
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Nutrition and Dietetics ,retinoids ,RBP4 ,retinol transport ,Tretinoin ,liver ,vitamin A ,retinoid homeostasis ,Mice ,Retinoids ,Liver ,Animals ,Homeostasis ,Humans ,Vitamin A ,metabolism ,Food Science - Abstract
Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations. Version of record
- Published
- 2022
30. Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice
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Renate Schreiber, Dominik Bulfon, Lisa M. Pusch, Gabriele Schoiswohl, Gunther Marsche, Gernot F. Grabner, Ulrike Taschler, Martina Schweiger, Achim Lass, Robert Zimmermann, Harald Koefeler, Nermeen Fawzy, and Thomas O. Eichmann
- Subjects
0301 basic medicine ,insulin ,Endosome ,Phospholipid ,Adipose tissue ,Endosomes ,QD415-436 ,030204 cardiovascular system & hematology ,liver ,Biochemistry ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Lysosome ,lipid metabolism ,Brown adipose tissue ,medicine ,Animals ,pancreas ,Research Articles ,phospholipids ,nutritional state ,Chemistry ,Macrophages ,Lipid metabolism ,Cell Biology ,Metabolism ,adipose tissue ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,embryonic structures ,lysosome ,Monoglycerides ,Lysophospholipids ,Lysosomes ,body temperature ,Plant lipid transfer proteins - Abstract
Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid, is a phospholipid that promotes lipid sorting in late endosomes/lysosomes by activating lipid hydrolases and lipid transfer proteins. Changes in the cellular BMP content therefore reflect an altered metabolic activity of the endolysosomal system. Surprisingly, little is known about the physiological regulation of BMP. In this study, we investigated the effects of nutritional and metabolic factors on BMP profiles of whole tissues and parenchymal and nonparenchymal cells. Tissue samples were obtained from fed, fasted, 2 h refed, and insulin-treated mice, as well as from mice housed at 5°C, 22°C, or 30°C. These tissues exhibited distinct BMP profiles that were regulated by the nutritional state in a tissue-specific manner. Insulin treatment was not sufficient to mimic refeeding-induced changes in tissue BMP levels, indicating that BMP metabolism is regulated by other hormonal or nutritional factors. Tissue fractionation experiments revealed that fasting drastically elevates BMP levels in hepatocytes and pancreatic cells. Furthermore, we observed that the BMP content in brown adipose tissue strongly depends on housing temperatures. In conclusion, our observations suggest that BMP concentrations adapt to the metabolic state in a tissue- and cell-type-specific manner in mice. Drastic changes observed in hepatocytes, pancreatic cells, and brown adipocytes suggest that BMP plays a role in the functional adaption to nutrient starvation and ambient temperature.
- Published
- 2020
31. KIAA1363 affects retinyl ester turnover in cultured murine and human hepatic stellate cells
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Carina Wagner, Victoria Hois, Annalena Eggeling, Lisa-Maria Pusch, Laura Pajed, Patrick Starlinger, Thierry Claudel, Michael Trauner, Robert Zimmermann, Ulrike Taschler, and Achim Lass
- Subjects
Mice ,Retinyl Esters ,Endocrinology ,Liver ,Hydrolases ,Hepatic Stellate Cells ,Animals ,Humans ,Cell Biology ,Sterol Esterase ,Vitamin A ,Biochemistry ,Carboxylic Ester Hydrolases - Abstract
Large quantities of vitamin A are stored as retinyl esters (REs) in specialized liver cells, the hepatic stellate cells (HSCs). To date, the enzymes controlling RE degradation in HSCs are poorly understood. In this study, we identified KIAA1363 (also annotated as arylacetamide deacetylase 1 or neutral cholesterol ester hydrolase 1) as a novel RE hydrolase. We show that KIAA1363 is expressed in the liver, mainly in HSCs, and exhibits RE hydrolase activity at neutral pH. Accordingly, addition of the KIAA1363-specific inhibitor JW480 largely reduced RE hydrolase activity in lysates of cultured murine and human HSCs. Furthermore, cell fractionation experiments and confocal microscopy studies showed that KIAA1363 localizes to the endoplasmic reticulum. We demonstrate that overexpression of KIAA1363 in cells led to lower cellular RE content after a retinol loading period. Conversely, pharmacological inhibition or shRNA-mediated silencing of KIAA1363 expression in cultured murine and human HSCs attenuated RE degradation. Together, our data suggest that KIAA1363 affects vitamin A metabolism of HSCs by hydrolyzing REs at the endoplasmic reticulum, thereby counteracting retinol esterification and RE storage in lipid droplets.
- Published
- 2021
32. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity
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Anne Fougerat, Gabriele Schoiswohl, Arnaud Polizzi, Marion Régnier, Carina Wagner, Sarra Smati, Tiffany Fougeray, Yannick Lippi, Frederic Lasserre, Ilyès Raho, Valentine Melin, Blandine Tramunt, Raphaël Métivier, Caroline Sommer, Fadila Benhamed, Chantal Alkhoury, Franziska Greulich, Céline Jouffe, Anthony Emile, Michael Schupp, Pierre Gourdy, Patricia Dubot, Thierry Levade, Delphine Meynard, Sandrine Ellero-Simatos, Laurence Gamet-Payrastre, Ganna Panasyuk, Henriette Uhlenhaut, Ez-Zoubir Amri, Céline Cruciani-Guglielmacci, Catherine Postic, Walter Wahli, Nicolas Loiseau, Alexandra Montagner, Dominique Langin, Achim Lass, Hervé Guillou, Graz University of Technology [Graz] (TU Graz), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Nanyang Technological University [Singapour], University of Lausanne (UNIL), BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität [Graz, Autriche]-Medical University Graz, Région Occitanie, FRM (FDM201906008682), Boulos Foundation, ERC-2018-COG-MetaboSENS-819543, German Research Foundation (DFG) (SCH 2546/5-1), the Leuchtturmprojekt/Flagship Project 'Lipases and Lipid Signaling' funded by BioTechMed-Graz, ANR-16-CE14-0029,NUTRISENSPIK,Déterminants moléculaires de l'homéostasie hépatique nutritive(2016), ANR-17-CE14-0015,HepAdialogue,Impact du métabolisme des acides gras des tissus adipeux et du foie sur l'insulinorésistance(2017), ANR-21-CE14-0079,Hepatologic,Réseau de controle des réponses transcriptionnelles hépatiques aux challenges nutritionnels par des récepteurs nucléaires(2021), European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Medical University of Graz, Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Diabétologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Helmholtz Zentrum München = German Research Center for Environmental Health, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lee Kong Chian School of Medicine, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Technische Universität Graz (TU Graz), Région Occitanie B.T. was supported by FRM (FDM201906008682)., Boulos Foundation and FRM., German Research Foundation (DFG) (SCH 2546/5-1 to M.S.), I3535, andP34899 (A.L.) by Austrian Science Fund (FWF, ERC-2018-COG-MetaboSENS- 819543 (G.P.), the Leuchtturmprojekt/Flagship Project ‘‘Lipases and Lipid Signaling’’ (A.L.), funded by BioTechMed-Graz, and by P28882-B21 (G.S.), European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, LESUR, Hélène, Impact du métabolisme des acides gras des tissus adipeux et du foie sur l'insulinorésistance - - HepAdialogue2017 - ANR-17-CE14-0015 - AAPG2017 - VALID, Réseau de controle des réponses transcriptionnelles hépatiques aux challenges nutritionnels par des récepteurs nucléaires - - Hepatologic2021 - ANR-21-CE14-0079 - AAPG2021 - VALID, Déterminants moléculaires de l'homéostasie hépatique nutritive - - NUTRISENSPIK2016 - ANR-16-CE14-0029 - AAPG2016 - VALID, and AgreenSkills+ - AGREENSKILLSPLUS - - EC:FP7:PEOPLE2014-05-05 - 2019-05-04 - 609398 - VALID
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fasting ,[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Adipose Tissue, White ,Metabolism ,Fgf21 ,Pparα ,Fasting ,Ketogenesis ,Lipolysis [Atgl ,Cp] ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Ketone Bodies ,[SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,PPARα ,General Biochemistry, Genetics and Molecular Biology ,ATGL ,FGF21 ,Adipose Tissue, Brown ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,PPAR alpha ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,CP: Metabolism ,ketogenesis ,[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,Adipose Tissue ,Hepatocytes ,lipolysis ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the β3-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.
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- 2022
33. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity
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Marion Régnier, Ganna Panasyuk, Michael Schupp, Yannick Lippi, Arnaud Polizzi, Chantal Alkhoury, Tiffany Fougeray, Patricia Dubot, Anne Fougerat, Sarra Smati, Anthony Emile, Gabriele Schoiswohl, Laurence Gamet-Payrastre, Carina Wagner, Valentine Melin, Catherine Postic, Nicolas Loiseau, Blandine Tramunt, Sandrine Ellero-Simatos, Ez-Zoubir Amri, Walter Wahli, Achim Lass, Dominique Langin, Alexandra Montagner, Hervé Guillou, Pierre Gourdy, Thierry Levade, and Frédéric Lasserre
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medicine.medical_specialty ,FGF21 ,Adipose tissue ,White adipose tissue ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Adipocyte ,Internal medicine ,Hepatocyte ,Adipose triglyceride lipase ,Brown adipose tissue ,medicine ,Lipolysis - Abstract
ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor α (PPARα) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPARα has not been investigated.MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPARα. Finally, we tested the consequences of hepatocyte-specific PPARα deficiency during pharmacological induction of adipocyte lipolysis with a β3-adrenergic receptor agonist.ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPARα target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPARα. Adipose tissue lipolysis induced by acute activation of the β3-adrenergic receptor also triggered PPARα-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPARα activity. In addition, the absence of hepatocyte PPARα altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the β3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPARα showed decreased tolerance to acute cold exposure.ConclusionsThese results underscore the central role of hepatocyte PPARα in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPARα activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.
- Published
- 2021
34. Advanced lipodystrophy reverses fatty liver in mice lacking adipocyte hormone-sensitive lipase
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Laura Pajed, Ulrike Taschler, Anna Tilp, Peter Hofer, Petra Kotzbeck, Stephanie Kolleritsch, Franz P. W. Radner, Isabella Pototschnig, Carina Wagner, Margarita Schratter, Sandra Eder, Sabrina Huetter, Renate Schreiber, Guenter Haemmerle, Thomas O. Eichmann, Martina Schweiger, Gerald Hoefler, Erin E. Kershaw, Achim Lass, and Gabriele Schoiswohl
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Blood Glucose ,Male ,Mice, Knockout ,Time Factors ,Lipodystrophy ,QH301-705.5 ,Lipolysis ,Age Factors ,food and beverages ,Type 2 diabetes ,Sterol Esterase ,Article ,Fatty Liver ,Mice, Inbred C57BL ,PPAR gamma ,Disease Models, Animal ,Liver ,Adipocytes ,Animals ,Insulin ,Biology (General) ,Energy Metabolism ,Non-alcoholic fatty liver disease - Abstract
Modulation of adipocyte lipolysis represents an attractive approach to treat metabolic diseases. Lipolysis mainly depends on two enzymes: adipose triglyceride lipase and hormone-sensitive lipase (HSL). Here, we investigated the short- and long-term impact of adipocyte HSL on energy homeostasis using adipocyte-specific HSL knockout (AHKO) mice. AHKO mice fed high-fat-diet (HFD) progressively developed lipodystrophy accompanied by excessive hepatic lipid accumulation. The increased hepatic triglyceride deposition was due to induced de novo lipogenesis driven by increased fatty acid release from adipose tissue during refeeding related to defective insulin signaling in adipose tissue. Remarkably, the fatty liver of HFD-fed AHKO mice reversed with advanced age. The reversal of fatty liver coincided with a pronounced lipodystrophic phenotype leading to blunted lipolytic activity in adipose tissue. Overall, we demonstrate that impaired adipocyte HSL-mediated lipolysis affects systemic energy homeostasis in AHKO mice, whereby with older age, these mice reverse their fatty liver despite advanced lipodystrophy., Pajed et al. investigate the role of adipocyte hormone-sensitive lipase (HSL) in whole body energy homeostasis. They show that adipocyte-specific HSL Knockout (AHKO) mice fed high fat diet develop fatty liver. Interestingly, this phenotype reverses in aged AHKO mice, possibly due to blunted lipolytic activity in adipose tissue with pronounced lipodystrophy.
- Published
- 2020
35. Abnormal composition and function of high‐density lipoproteins in atopic dermatitis patients
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Eva Knuplez, Markus Trieb, Rufina Schuligoi, Thomas O. Eichmann, Michael Holzer, Christian Schuster, Miriam Peinhaupt, Achim Lass, Akos Heinemann, Wolfgang Weger, Peter Wolf, Christian Wadsack, Gunther Marsche, and Athina Trakaki
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0301 basic medicine ,Immunology ,High density ,Hdl metabolism ,Dermatitis, Atopic ,Immunomodulation ,03 medical and health sciences ,Disease susceptibility ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Humans ,Letters to the Editor ,Letter to the Editor ,business.industry ,Lipid metabolism ,Atopic dermatitis ,medicine.disease ,Lipid Metabolism ,030104 developmental biology ,030220 oncology & carcinogenesis ,Composition (visual arts) ,Disease Susceptibility ,business ,Lipoproteins, HDL ,Function (biology) ,Biomarkers - Published
- 2018
36. Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice
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Chaitanya Chakravarthi, Gali, Elham, Fanaee-Danesh, Martina, Zandl-Lang, Nicole Maria, Albrecher, Carmen, Tam-Amersdorfer, Anika, Stracke, Vinay, Sachdev, Florian, Reichmann, Yidan, Sun, Afrim, Avdili, Marielies, Reiter, Dagmar, Kratky, Peter, Holzer, Achim, Lass, Karunya K, Kandimalla, and Ute, Panzenboeck
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Male ,Amyloid beta-Peptides ,Amyloid-β peptides ,Swine ,Endothelial cells ,Alzheimer's disease ,Receptor, Insulin ,Article ,Mice, Inbred C57BL ,Insulin signaling ,Mice ,Low-density lipoprotein receptor-related protein-1 ,Autophagy ,Autophagy-lysosomal pathway ,Animals ,Humans ,Insulin ,lipids (amino acids, peptides, and proteins) ,Female ,Insulin receptor-beta ,Lysosomes ,Low Density Lipoprotein Receptor-Related Protein-1 ,Cells, Cultured ,Signal Transduction ,Blood-brain barrier - Abstract
Aberrant insulin signaling constitutes an early change in Alzheimer's disease (AD). Insulin receptors (IR) and low-density lipoprotein receptor-related protein-1 (LRP-1) are expressed in brain capillary endothelial cells (BCEC) forming the blood-brain barrier (BBB). There, insulin may regulate the function of LRP-1 in Aβ clearance from the brain. Changes in IR-β and LRP-1 and insulin signaling at the BBB in AD are not well understood. Herein, we identified a reduction in cerebral and cerebrovascular IR-β levels in 9-month-old male and female 3XTg-AD (PS1M146V, APPSwe, and tauP301L) as compared to NTg mice, which is important in insulin mediated signaling responses. Reduced cerebral IR-β levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-β and LRP-1 levels in 3XTg-AD mice correlated with elevated levels of autophagy marker LC3B. In both genotypes, high-fat diet (HFD) feeding decreased cerebral and hepatic LRP-1 expression and elevated cerebral Aβ burden without affecting cerebrovascular LRP-1 and IR-β levels. In vitro studies using primary porcine (p)BCEC revealed that Aβ peptides 1–40 or 1–42 (240 nM) reduced cellular levels and interaction of LRP-1 and IR-β thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that Aβ treatment accelerated the autophagy-lysosomal degradation of IR-β and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-β levels through post-translational pathways further deteriorating insulin-mediated responses at the BBB. Our findings indicate that LRP-1 proves important for insulin signaling at the BBB. Cerebral Aβ burden in AD may accelerate LRP-1 and IR-β degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.
- Published
- 2019
37. Hepatocyte-specific deletion of lysosomal acid lipase leads to cholesteryl ester but not triglyceride or retinyl ester accumulation
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Laura, Pajed, Carina, Wagner, Ulrike, Taschler, Renate, Schreiber, Stephanie, Kolleritsch, Nermeen, Fawzy, Isabella, Pototschnig, Gabriele, Schoiswohl, Lisa-Maria, Pusch, Beatrix I, Wieser, Paul, Vesely, Gerald, Hoefler, Thomas O, Eichmann, Robert, Zimmermann, and Achim, Lass
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Mice, Knockout ,cholesterol ,Sterol Esterase ,Diet, High-Fat ,liver ,Lipids ,vitamin A ,Mice, Inbred C57BL ,Mice ,lipid metabolism ,CCAAT-Enhancer-Binding Proteins ,Hepatocytes ,lysosome ,lysosomal acid lipase ,Animals ,Cholesterol Esters ,triglyceride ,neutral lipid ester metabolism ,Diterpenes ,hyperlipidemia, metabolic disorder ,Cells, Cultured ,Phospholipids ,Triglycerides - Abstract
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl ester (CE) and retinyl ester (RE) and triglyceride (TG). Mice globally lacking LAL accumulate CE most prominently in the liver. The severity of the CE accumulation phenotype progresses with age and is accompanied by hepatomegaly and hepatic cholesterol crystal deposition. In contrast, hepatic TG accumulation is much less pronounced in these mice, and hepatic RE levels are even decreased. To dissect the functional role of LAL for neutral lipid ester mobilization in the liver, we generated mice specifically lacking LAL in hepatocytes (hep-LAL-ko). On a standard chow diet, hep-LAL-ko mice exhibited increased hepatic CE accumulation but unaltered TG and RE levels. Feeding the hep-LAL-ko mice a vitamin A excess/high-fat diet (VitA/HFD) further increased hepatic cholesterol levels, but hepatic TG and RE levels in these mice were lower than in control mice. Performing in vitro activity assays with lysosome-enriched fractions from livers of mice globally lacking LAL, we detected residual acid hydrolytic activities against TG and RE. Interestingly, this non-LAL acid TG hydrolytic activity was elevated in lysosome-enriched fractions from livers of hep-LAL-ko mice upon VitA/HFD feeding. In conclusion, the neutral lipid ester phenotype in livers from hep-LAL-ko mice indicates that LAL is limiting for CE turnover, but not for TG and RE turnovers. Furthermore, in vitro hydrolase activity assays revealed the existence of non-LAL acid hydrolytic activities for TG and RE. The corresponding acid lipase(s) catalyzing these reactions remains to be identified.
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- 2018
38. A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics
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Zhuyin Li, Mathias Beller, Douglas S. Auld, Li Liu, Kirsten Tschapalda, Carole Sztalryd, Herbert Waldmann, Thomas O. Eichmann, Slava Ziegler, Matthew B. Boxer, Thomas Schlemper, Yaqin Zhang, Min Shen, Urmila Sreenivasan, Achim Lass, Kseniya Golovnina, John C. McLenithan, Brian Oliver, and Madhu Lal-Nag
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Male ,0301 basic medicine ,High-throughput screening ,lcsh:Medicine ,Genomics ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Medicine, General & Internal ,In vivo ,Chlorocebus aethiops ,Animals ,Humans ,Structure–activity relationship ,Pyrroles ,Diacylglycerol O-Acyltransferase ,Enzyme Inhibitors ,Genetics ,chemistry.chemical_classification ,lcsh:R5-920 ,Sequence Analysis, RNA ,Fatty Acids ,lcsh:R ,Cell Differentiation ,Epistasis, Genetic ,General Medicine ,Phenotype ,Small molecule ,3. Good health ,030104 developmental biology ,Enzyme ,Biochemistry ,chemistry ,COS Cells ,Epistasis ,Drosophila ,Female ,lipids (amino acids, peptides, and proteins) ,Lipid Peroxidation ,lcsh:Medicine (General) ,Research Paper - Abstract
Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened > 320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests., Highlights • We identified > 600 potent small molecule inhibitors of cellular lipid storage deposition. • RNA-Seq expression profiling discriminated the activity of three lead scaffolds and guided subsequent functional studies. • We discovered a class of DGAT1 inhibitors, which is active in fly and mammalian cell lines as well as whole flies. Obesity and other lipid storage associated diseases are a growing health threat of human populations. In an undirected phenotypic screen, we identified pharmacologically active small molecules that reduce or enhance lipid storage. Our work focuses on three lead structures that prevent lipid storage in diverse cellular systems including cells from a diabetes patient. In order to elucidate the compound mechanisms-of-action and cellular targets, we used a combination of RNA-Seq transcriptional profiling and diverse functional assays. Our results strongly suggest that one of our lead structures represents a class of inhibitors targeting the key lipogenic enzyme diacylglycerol acyltransferase 1.
- Published
- 2016
39. Lysosomal acid lipase is the major acid retinyl ester hydrolase in cultured human hepatic stellate cells but not essential for retinyl ester degradation
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Robert Zimmermann, Carina Wagner, Laura Pajed, Victoria Hois, Achim Lass, Michael Trauner, Lisa-Maria Pusch, Heimo Wolinski, and Ulrike Taschler
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0301 basic medicine ,Retinyl ester ,Phospholipase ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Lipid droplet ,Hydrolase ,Hepatic Stellate Cells ,Animals ,Humans ,Lipase ,Vitamin A ,Molecular Biology ,Hepatic stellate cell ,Cells, Cultured ,Mice, Knockout ,biology ,Retinol ,Chemistry ,Cell Biology ,Sterol Esterase ,In vitro ,030104 developmental biology ,Liver ,Biochemistry ,Adipose triglyceride lipase ,biology.protein ,030211 gastroenterology & hepatology ,Carboxylic Ester Hydrolases - Abstract
Vitamin A is stored as retinyl esters (REs) in lipid droplets of hepatic stellate cells (HSCs). To date, two different pathways are known to facilitate the breakdown of REs: (i) Hydrolysis of REs by neutral lipases, and (ii) whole lipid droplet degradation in autolysosomes by acid hydrolysis. In this study, we evaluated the contribution of neutral and acid RE hydrolases to the breakdown of REs in human HSCs. (R)-Bromoenol lactone (R-BEL), inhibitor of adipose triglyceride lipase (ATGL) and patatin-like phospholipase domain-containing 3 (PNPLA3), the hormone-sensitive lipase (HSL) inhibitor 76-0079, as well as the serine-hydrolase inhibitor Orlistat reduced neutral RE hydrolase activity of LX-2 cell-lysates between 20 and 50%. Interestingly, in pulse-chase experiments, R-BEL, 76-0079, as well as Orlistat exerted little to no effect on cellular RE breakdown of LX-2 cells as well as primary human HSCs. In contrast, Lalistat2, a specific lysosomal acid lipase (LAL) inhibitor, virtually blunted acid in vitro RE hydrolase activity of LX-2 cells. Accordingly, HSCs isolated from LAL-deficient mice showed RE accumulation and were virtually devoid of acidic RE hydrolase activity. In pulse-chase experiments however, LAL-deficient HSCs, similar to LX-2 cells and primary human HSCs, were not defective in degrading REs. In summary, results demonstrate that ATGL, PNPLA3, and HSL cfontribute to neutral RE hydrolysis of human HSCs. LAL is the major acid RE hydrolase in HSCs. Yet, LAL is not limiting for RE degradation under serum-starvation. Together, results suggest that RE breakdown of HSCs is facilitated by (a) so far unknown, non-Orlistat inhibitable RE-hydrolase(s).
- Published
- 2020
40. Genetically modified mouse models to study hepatic neutral lipid mobilization
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Guenter Haemmerle and Achim Lass
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0301 basic medicine ,medicine.medical_specialty ,Cirrhosis ,Article ,03 medical and health sciences ,Liver disease ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Lipid droplet ,Internal medicine ,medicine ,Animals ,Humans ,Molecular Biology ,business.industry ,Liver Diseases ,Fatty liver ,Lipase ,medicine.disease ,Lipid Metabolism ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Liver ,Cholesteryl ester ,Hepatic stellate cell ,Molecular Medicine ,030211 gastroenterology & hepatology ,lipids (amino acids, peptides, and proteins) ,Steatosis ,Steatohepatitis ,business - Abstract
Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.
- Published
- 2018
41. Reduced Incorporation of Fatty Acids Into Triacylglycerol in Myotubes From Obese Individuals With Type 2 Diabetes
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Esther Moonen-Kornips, L. Bilet, Gert Schaart, Madeleen Bosma, Patrick Schrauwen, Thomas O. Eichmann, Achim Lass, Tineke van de Weijer, Bram Brouwers, Lauren M. Sparks, Matthijs K. C. Hesselink, Humane Biologie, Nutrition and Movement Sciences, Bewegingswetenschappen, RS: NUTRIM - R1 - Metabolic Syndrome, and RS: NUTRIM - HB/BW section B
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Adult ,Male ,EXPRESSION ,Muscle tissue ,medicine.medical_specialty ,MUSCLE INSULIN-RESISTANCE ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Muscle Fibers, Skeletal ,Palmitates ,Type 2 diabetes ,Biology ,OXIDATION ,Article ,GLUCOSE ,LIPID-METABOLISM ,In vivo ,Internal medicine ,Internal Medicine ,medicine ,Obesity ,Muscle, Skeletal ,Triglycerides ,SPECTROSCOPY ,Muscle biopsy ,medicine.diagnostic_test ,Myogenesis ,Fatty Acids ,nutritional and metabolic diseases ,Skeletal muscle ,HUMANS ,Lipid metabolism ,Middle Aged ,QUANTIFICATION ,Lipid Metabolism ,medicine.disease ,Control subjects ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,SKELETAL-MUSCLE ,SENSITIVITY ,human activities - Abstract
Altered skeletal muscle lipid metabolism is a hallmark feature of type 2 diabetes (T2D). We investigated muscle lipid turnover in T2D versus BMI-matched control subjects (controls) and examined whether putative in vivo differences would be preserved in the myotubes. Male obese T2D individuals (n = 6) and BMI-matched controls (n = 6) underwent a hyperinsulinemic-euglycemic clamp, VO2max test, dual-energy X-ray absorptiometry scan, underwater weighing, and muscle biopsy of the vastus lateralis. 14C-palmitate and 14C-oleate oxidation rates and incorporation into lipids were measured in muscle tissue as well as in primary myotubes. Palmitate oxidation (controls: 0.99 ± 0.17 nmol/mg protein; T2D: 0.53 ± 0.07 nmol/mg protein; P = 0.03) and incorporation of fatty acids (FAs) into triacylglycerol (TAG) (controls: 0.45 ± 0.13 nmol/mg protein; T2D: 0.11 ± 0.02 nmol/mg protein; P = 0.047) were significantly reduced in muscle homogenates of T2D. These reductions were not retained for palmitate oxidation in primary myotubes (P = 0.38); however, incorporation of FAs into TAG was lower in T2D (P = 0.03 for oleate and P = 0.11 for palmitate), with a strong correlation of TAG incorporation between muscle tissue and primary myotubes (r = 0.848, P = 0.008). The data indicate that the ability to incorporate FAs into TAG is an intrinsic feature of human muscle cells that is reduced in individuals with T2D.
- Published
- 2014
42. Fat-specific Protein 27 (FSP27) Interacts with Adipose Triglyceride Lipase (ATGL) to Regulate Lipolysis and Insulin Sensitivity in Human Adipocytes
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Cynthia M. Smas, Martina Schweiger, Vishva M. Sharma, Achim Lass, Rudolf Zechner, Jun Yin, Mi-Jeong Lee, Tan Hooi Min Grahn, Rajween Kaur, Yasuo Ido, and Vishwajeet Puri
- Subjects
medicine.medical_specialty ,Lipolysis ,Biochemistry ,Mice ,chemistry.chemical_compound ,Insulin resistance ,3T3-L1 Cells ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Animals ,Humans ,Insulin ,Phosphorylation ,Molecular Biology ,Triglycerides ,Mice, Knockout ,chemistry.chemical_classification ,biology ,Triglyceride ,Fatty acid metabolism ,Chemistry ,Proteins ,Fatty acid ,Lipase ,Cell Biology ,medicine.disease ,Insulin receptor ,Endocrinology ,Adipose triglyceride lipase ,biology.protein ,Insulin Resistance ,Apoptosis Regulatory Proteins ,Protein Binding ,Signal Transduction - Abstract
In adipocytes, lipolysis is a highly regulated process involving hormonal signals, lipid droplet-associated proteins, and lipases. The discovery of new lipid droplet-associated proteins added complexity to the current model of lipolysis. In this study, we used cultured human adipocytes to demonstrate that fat-specific protein 27 (FSP27), an abundantly expressed protein in adipocytes, regulates both basal and stimulated lipolysis by interacting with adipose triglyceride lipase (ATGL, also called desnutrin or PNPLA2). We identified a core domain of FSP27, amino acids 120-220, that interacts with ATGL to inhibit its lipolytic function and promote triglyceride storage. We also defined the role of FSP27 in free fatty acid-induced insulin resistance in adipocytes. FSP27 depletion in human adipocytes increased lipolysis and inhibited insulin signaling by decreasing AKT phosphorylation. However, reducing lipolysis by either depletion of ATGL or expression of exogenous full-length FSP27 or amino acids 120-220 protected human adipocytes against the adverse effects of free fatty acids on insulin signaling. In embryonic fibroblasts derived from ATGL KO mice, exogenous free fatty acids did not affect insulin sensitivity. Our results demonstrate a crucial role for FSP27-ATGL interactions in regulating lipolysis, triglyceride accumulation, and insulin signaling in human adipocytes.
- Published
- 2014
43. Fat in the skin: Triacylglycerol metabolism in keratinocytes and its role in the development of neutral lipid storage disease
- Author
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Franz Pw Radner, Achim Lass, Susanne Grond, Rudolf Zechner, and Guenter Haemmerle
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0303 health sciences ,Ceramide ,Corneocyte ,Endocrinology, Diabetes and Metabolism ,Dermatology ,Biology ,Lamellar granule ,medicine.disease ,Neutral lipid storage disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Stratum corneum ,medicine ,lipids (amino acids, peptides, and proteins) ,Sphingomyelin ,Keratinocyte ,030217 neurology & neurosurgery ,030304 developmental biology ,Diacylglycerol kinase - Abstract
Keratinocyte differentiation is essential for skin development and the formation of the skin permeability barrier. This process involves an orchestrated remodeling of lipids. The cleavage of precursor lipids from lamellar bodies by β-glucocerebrosidase, sphingomyelinase, phospholipases and sterol sulfatase generates ceramides, non-esterified fatty acids and cholesterol for the lipid-containing extracellular matrix, the lamellar membranes in the stratum corneum. The importance of triacylglycerol (TAG) hydrolysis for the formation of a functional permeability barrier was only recently appreciated. Mice with defects in TAG synthesis (acyl-CoA:diacylglycerol acyltransferase-2-knock-out) or TAG catabolism (comparative gene identification-58, -CGI-58-knock-out) develop severe permeability barrier defects and die soon after birth because of desiccation. In humans, mutations in the CGI-58 gene also cause (non-lethal) neutral lipid storage disease with ichthyosis. As a result of defective TAG synthesis or catabolism, humans and mice lack ω-(O)-acylceramides, which are essential lipid precursors for the formation of the corneocyte lipid envelope. This structure plays an important role in linking the lipid-enriched lamellar membranes to highly cross-linked corneocyte proteins. This review focuses on the current knowledge of biochemical mechanisms that are essential for epidermal neutral lipid metabolism and the formation of a functional skin permeability barrier.
- Published
- 2014
- Full Text
- View/download PDF
44. Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice
- Author
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Nemanja, Vujic, Melanie, Korbelius, Christina, Leopold, Madalina, Duta-Mare, Silvia, Rainer, Stefanie, Schlager, Madeleine, Goeritzer, Dagmar, Kolb, Thomas O, Eichmann, Clemens, Diwoky, Andreas, Zimmer, Robert, Zimmermann, Achim, Lass, Branislav, Radovic, and Dagmar, Kratky
- Subjects
Male ,desensitization ,Asialoglycoproteins ,Membrane Proteins ,cholesterol ,cannabinoid receptor ,Arachidonic Acids ,endocannabinoid ,Atherosclerosis ,Glycerides ,Alcohol Oxidoreductases ,Disease Models, Animal ,Gene Knockout Techniques ,Mice ,Apolipoproteins E ,Liver ,lipolysis ,Animals ,lipids (amino acids, peptides, and proteins) ,Lectins, C-Type ,Intestinal Mucosa ,Dyslipidemias ,Endocannabinoids ,Research Paper - Abstract
Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (−/−) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)−/− mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.
- Published
- 2016
45. Studies on the Substrate and Stereo/Regioselectivity of Adipose Triglyceride Lipase, Hormone-sensitive Lipase, and Diacylglycerol-O-acyltransferases
- Author
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Thomas O. Eichmann, Rudolf Zechner, Robert V. Farese, Joel T. Haas, Manju Kumari, Achim Lass, and Robert Zimmermann
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Male ,genetic structures ,Lipolysis ,Hormone-sensitive lipase ,Biochemistry ,Mice ,Lipid droplet ,Chlorocebus aethiops ,Animals ,Protein Isoforms ,Diacylglycerol O-Acyltransferase ,Cloning, Molecular ,Lipase ,Molecular Biology ,Protein Kinase C ,Protein kinase C ,Glutathione Transferase ,Diacylglycerol kinase ,chemistry.chemical_classification ,biology ,urogenital system ,nutritional and metabolic diseases ,Fatty acid ,Stereoisomerism ,Cell Biology ,Sterol Esterase ,eye diseases ,Mice, Inbred C57BL ,Metabolism ,Adipose Tissue ,Models, Chemical ,chemistry ,Type C Phospholipases ,COS Cells ,Adipose triglyceride lipase ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Signal Transduction - Abstract
Adipose triglyceride lipase (ATGL) is rate-limiting for the initial step of triacylglycerol (TAG) hydrolysis, generating diacylglycerol (DAG) and fatty acids. DAG exists in three stereochemical isoforms. Here we show that ATGL exhibits a strong preference for the hydrolysis of long-chain fatty acid esters at the sn-2 position of the glycerol backbone. The selectivity of ATGL broadens to the sn-1 position upon stimulation of the enzyme by its co-activator CGI-58. sn-1,3 DAG is the preferred substrate for the consecutive hydrolysis by hormone-sensitive lipase. Interestingly, diacylglycerol-O-acyltransferase 2, present at the endoplasmic reticulum and on lipid droplets, preferentially esterifies sn-1,3 DAG. This suggests that ATGL and diacylglycerol-O-acyltransferase 2 act coordinately in the hydrolysis/re-esterification cycle of TAGs on lipid droplets. Because ATGL preferentially generates sn-1,3 and sn-2,3, it suggests that TAG-derived DAG cannot directly enter phospholipid synthesis or activate protein kinase C without prior isomerization.
- Published
- 2012
46. PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides
- Author
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Susanne, Grond, Thomas O, Eichmann, Sandrine, Dubrac, Dagmar, Kolb, Matthias, Schmuth, Judith, Fischer, Debra, Crumrine, Peter M, Elias, Guenter, Haemmerle, Rudolf, Zechner, Achim, Lass, and Franz P W, Radner
- Subjects
Mice, Inbred C57BL ,Mice ,integumentary system ,Animals ,Ichthyosis ,Lipase ,Ceramides ,Permeability ,Article ,Skin - Abstract
Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.
- Published
- 2016
47. Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation
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Susanne, Grond, Franz P W, Radner, Thomas O, Eichmann, Dagmar, Kolb, Gernot F, Grabner, Heimo, Wolinski, Robert, Gruber, Peter, Hofer, Christoph, Heier, Silvia, Schauer, Thomas, Rülicke, Gerald, Hoefler, Matthias, Schmuth, Peter M, Elias, Achim, Lass, Rudolf, Zechner, and Guenter, Haemmerle
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Keratinocytes ,integumentary system ,Cell Differentiation ,Lipase ,1-Acylglycerol-3-Phosphate O-Acyltransferase ,Ceramides ,humanities ,Article ,Mice ,health services administration ,mental disorders ,Animals ,Triglycerides ,Skin - Abstract
Adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) are limiting in cellular triglyceride catabolism. Although ATGL deficiency is compatible with normal skin development, mice globally lacking CGI-58 die postnatally and exhibit a severe epidermal permeability barrier defect, which may originate from epidermal and/or peripheral changes in lipid and energy metabolism. Here, we show that epidermis-specific disruption of CGI-58 is sufficient to provoke a defect in the formation of a functional corneocyte lipid envelope linked to impaired ω-O-acylceramide synthesis. As a result, epidermis-specific CGI-58-deficient mice show severe skin dysfunction, arguing for a tissue autonomous cause of disease development. Defective skin permeability barrier formation in global CGI-58-deficient mice could be reversed via transgenic restoration of CGI-58 expression in differentiated but not basal keratinocytes suggesting that CGI-58 is essential for lipid metabolism in suprabasal epidermal layers. The compatibility of ATGL deficiency with normal epidermal function indicated that CGI-58 may stimulate an epidermal triglyceride lipase beyond ATGL required for the adequate provision of fatty acids as a substrate for ω-O-acylceramide synthesis. Pharmacological inhibition of ATGL enzyme activity similarly reduced triglyceride-hydrolytic activities in wild-type and CGI-58 overexpressing epidermis implicating that CGI-58 participates in ω-O-acylceramide biogenesis independent of its role as a coactivator of epidermal triglyceride catabolism.
- Published
- 2016
48. Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase
- Author
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Harald M. Nagy, Manju Kumari, Gabriele Schoiswohl, Gerald N. Rechberger, Achim Lass, Guenter Haemmerle, H. Alex Brown, Monika Oberer, Ruth Birner-Gruenberger, Ashraf Yusuf Rangrez, Erin E. Kershaw, Sarah A. Scott, Oskar Knittelfelder, Sandra Eder, Irina Cornaciu, Robert Zimmermann, Margret Paar, Pavlina T. Ivanova, Rudolf Zechner, Chandramohan Chitraju, and Nuttaporn Wongsiriroj
- Subjects
Male ,Models, Molecular ,Cirrhosis ,Physiology ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Dietary Sucrose ,Cricetinae ,Lysophosphatidic acid ,Chlorocebus aethiops ,Phospholipids ,Mice, Knockout ,0303 health sciences ,education.field_of_study ,Fatty liver ,Phosphatidic acid ,Hep G2 Cells ,1-Acylglycerol-3-Phosphate O-Acyltransferase ,Lipids ,3. Good health ,Up-Regulation ,Cysteine Endopeptidases ,Liver ,Acyltransferase ,COS Cells ,030211 gastroenterology & hepatology ,lipids (amino acids, peptides, and proteins) ,medicine.medical_specialty ,Phosphatidic Acids ,CHO Cells ,Biology ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Humans ,Adiponutrin ,education ,Molecular Biology ,Triglycerides ,030304 developmental biology ,Polymorphism, Genetic ,Membrane Proteins ,Lipid metabolism ,Cell Biology ,medicine.disease ,Lipid Metabolism ,Fatty Liver ,Endocrinology ,chemistry ,Acyl Coenzyme A ,Lysophospholipids ,Acyltransferases - Abstract
SummaryNumerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.
- Published
- 2012
- Full Text
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49. Remodeling of Lipid Droplets during Lipolysis and Growth in Adipocytes
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Andreas Zumbusch, Achim Lass, Heimo Wolinski, Christian Jüngst, Noemi A. Steiner, Christoph Magnes, Sepp D. Kohlwein, Frank Sinner, Dagmar Kolb, Robert Zimmermann, and Margret Paar
- Subjects
Time Factors ,Cell Survival ,Surface Properties ,Lipolysis ,Biology ,Biochemistry ,Mice ,chemistry.chemical_compound ,Fragmentation ,3T3-L1 Cells ,Lipid droplet ,Organelle ,Adipocytes ,Animals ,Humans ,CARS ,Fragmentation (cell biology) ,Fusion ,Molecular Biology ,Adipocyte ,Lipogenesis ,Stem Cells ,Lipid metabolism ,Lipid Droplets ,Cell Biology ,Lipid Metabolism ,Lipids ,Molecular Imaging ,Cell biology ,Triacsin C ,Lipotoxicity ,chemistry ,ddc:540 ,Time Lapse Imaging - Abstract
Background: Micro-lipid droplets (mLDs) appear in adipocytes upon lipolytic stimulation. LDs may grow by spontaneous, homotypic fusion. Results: Scavenging of fatty acids prevents mLD formation. LDs grow by a slow transfer of lipids between LDs. Conclusion: mLDs form due to fatty acid overflow. LD growth is a controlled process. Significance: Novel mechanistic insights into LD remodeling are provided., Synthesis, storage, and turnover of triacylglycerols (TAGs) in adipocytes are critical cellular processes to maintain lipid and energy homeostasis in mammals. TAGs are stored in metabolically highly dynamic lipid droplets (LDs), which are believed to undergo fragmentation and fusion under lipolytic and lipogenic conditions, respectively. Time lapse fluorescence microscopy showed that stimulation of lipolysis in 3T3-L1 adipocytes causes progressive shrinkage and almost complete degradation of all cellular LDs but without any detectable fragmentation into micro-LDs (mLDs). However, mLDs were rapidly formed after induction of lipolysis in the absence of BSA in the culture medium that acts as a fatty acid scavenger. Moreover, mLD formation was blocked by the acyl-CoA synthetase inhibitor triacsin C, implicating that mLDs are synthesized de novo in response to cellular fatty acid overload. Using label-free coherent anti-Stokes Raman scattering microscopy, we demonstrate that LDs grow by transfer of lipids from one organelle to another. Notably, this lipid transfer between closely associated LDs is not a rapid and spontaneous process but rather occurs over several h and does not appear to require physical interaction over large LD surface areas. These data indicate that LD growth is a highly regulated process leading to the heterogeneous LD size distribution within and between individual cells. Our findings suggest that lipolysis and lipogenesis occur in parallel in a cell to prevent cellular fatty acid overflow. Furthermore, we propose that formation of large LDs requires a yet uncharacterized protein machinery mediating LD interaction and lipid transfer.
- Published
- 2012
50. FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling
- Author
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Frank Madeo, Robert Zimmermann, Thomas O. Eichmann, Sepp D. Kohlwein, Rudolf Zechner, Achim Lass, and Guenter Haemmerle
- Subjects
Cell signaling ,Physiology ,Lipolysis ,Review ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Cellular metabolism ,Catabolism ,Chemistry ,Cellular lipid ,Lipid metabolism ,Lipase ,Cell Biology ,Lipid Metabolism ,Enzyme ,Biochemistry ,030220 oncology & carcinogenesis ,Adipose triglyceride lipase ,Signal Transduction - Abstract
Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that "lipolytic signaling" is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
- Published
- 2012
- Full Text
- View/download PDF
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