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Skeletal muscle dynamically regulates systemic nutrient homeostasis through transcriptional adaptations to physiological cues. In response to changes in the metabolic environment (e.g., alterations in circulating glucose or lipid levels), networks of transcription factors and coregulators are recruited to specific genomic loci to fine-tune homeostatic gene regulation. Elucidating these mechanisms is of particular interest as these gene regulatory pathways can serve as potential targets to treat metabolic disease. The zinc-finger transcription factor Krüppel-like factor 15 (KLF15) is a critical regulator of metabolic homeostasis; however, its genome-wide distribution in skeletal muscle has not been previously identified. Here, we characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We also identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ colocalize genome-wide, physically interact, and are dependent on one another to exert their transcriptional effects on target genes. These findings reveal that skeletal muscle KLF15 plays a critical role in metabolic adaptation through its direct actions on target genes and interactions with other nodal transcription factors such as PPARδ., Competing Interests: Conflict of interest S. M. H. is an executive, officer, and shareholder of Amgen and a scientific founder and shareholder of Tenaya Therapeutics. S. M. H. also serves on the Scientific Advisory Board for the German Centre for Cardiovascular Research of the German Ministry of Health (DZHK) on a voluntary and uncompensated basis. Z. J. is an employee of Biomarin. The other authors have declared that no conflict of interest exists., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Peroxisome Proliferator-Activated Receptors (PPARs) are a family of nuclear receptors that play essential roles in modulating cell differentiation, inflammation, and metabolism. Three subtypes of PPARs are known: PPAR-alpha (PPARα), PPAR-gamma (PPARγ), and PPAR-beta/delta (PPARβ/δ). PPARα activation reduces lipid levels and regulates energy homeostasis, activation of PPARγ results in regulation of adipogenesis, and PPARβ/δ activation increases fatty acid metabolism and lipolysis. PPARs are linked to various diseases, including but not limited to diabetes, non-alcoholic fatty liver disease, glaucoma and atherosclerosis. In the past decade, numerous studies have assessed the functional properties of PPARs in the eye and key PPAR mechanisms have been discovered, particularly regarding the retina and cornea. PPARγ and PPARα are well established in their functions in ocular homeostasis regarding neuroprotection, neovascularization, and inflammation, whereas PPARβ/δ isoform function remains understudied. Naturally, studies on PPAR agonists and antagonists, associated with ocular pathology, have also gained traction with the development of PPAR synthetic ligands. Studies on PPARs has significantly influenced novel therapeutics for diabetic eye disease, ocular neuropathy, dry eye, and age-related macular degeneration (AMD). In this review, therapeutic potentials and implications will be highlighted, as well as reported adverse effects. Further investigations are necessary before any of the PPARs ligands can be utilized, in the clinics, to treat eye diseases. Future research on the prominent role of PPARs will help unravel the complex mechanisms involved in order to prevent and treat ocular diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Over the last 30 years, nuclear receptors (NRs) have been increasingly recognized as key modulators of systemic homeostasis and as contributing factors in many diseases. In the kidney, NRs play numerous important roles in maintaining homeostasis-many of which continue to be unraveled. As "master regulators", these important transcription factors integrate and coordinate many renal processes such as circadian responses, lipid metabolism, fatty acid oxidation, glucose handling, and inflammatory responses. The use of recently-developed genetic tools and small molecule modulators have allowed for detailed studies of how renal NRs contribute to kidney homeostasis. Importantly, while NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases such as diabetes, acute kidney injury, and other conditions such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the role in health and disease of six key renal NRs including the peroxisome proliferator-activated receptors (PPAR), estrogen-related receptors (ERR), the farnesoid X receptors (FXR), estrogen receptors (ER), liver X receptors (LXR), and vitamin D receptors (VDR) with an emphasis on recent findings over the last decade. These NRs have generated a wealth of data over the last 10 years that demonstrate their crucial role in maintaining normal renal homeostasis as well as their capacity to modulate disease progression., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

It is becoming clear that several human pathologies are caused by altered metabolic adaptations. During liver development, there are physiological changes, from the predominant utilization of glucose (fetal life) to the use of lipids (postnatal life). Fasting is another physiological stress that elicits well-known metabolic adjustments. We have reported the metabolic properties of cardiotrophin-1 (CT-1), a member of the interleukin-6 family of cytokines. Here, we aimed at analyzing the role of CT-1 in response to these metabolic changes. We used different in vivo models. Furthermore, a differential study was carried out with wild-type and CT-1 null mice in fed (ad libitum) and food-restricted conditions. We demonstrated that Ct-1 is a metabolic gene induced in the liver via PPARα in response to lipids in mice (neonates- and food-restricted adults). We found that Ct-1 mRNA expression in white adipose tissue directly involved PPARα and PPARγ. Finally, the physiological role of CT-1 in fasting is confirmed by the impaired food restriction-induced adipose tissue lipid mobilization in CT-1 null mice. Our findings support a previously unrecognized physiological role of CT-1 in metabolic adaptations, through the regulation of lipid metabolism and contributes to fasting-induced free fatty acid mobilization., (© 2020 Federation of American Societies for Experimental Biology.)

Aims: It has been hypothesized that the activity of lysosomal acid lipase (LAL), a key enzyme involved in lipid metabolism, is involved in the NAFLD phenotype. To clarify the role of LAL in NAFLD, we studied 164 consecutive patients with biopsy-proven NAFLD and fat-loaded HepG2 cells., Methods: LAL activity was measured (i) on dried blood spots (DBS) from NAFLD patients and dyslipidemic subjects without fatty liver and (ii) on liver biopsies from NAFLD patients. LAL activity and expression were evaluated in HepG2 cells cultured in the presence of free fatty acids (FAs), with or without a PPAR-alpha agonist., Results: LAL activity was significantly reduced in patients with NAFLD compared to dyslipidemic subjects. LAL activity measured in liver biopsies from NAFLD patients was highly correlated to that measured on DBS and was independent of LAL expression in the liver. In a fully adjusted model, LAL activity on DBS was associated only with platelets and, when normalized by platelet count, it did not differ according to fibrosis stage. In vitro, FA loading of HepG2 fully replicated the impairment of LAL activity observed in NALFD patients. In these cells, the activation of PPAR-alpha receptors prevented and corrected FA-induced LAL impairment, by stimulating FA oxidation and LAL expression., Conclusions: LAL activity is reduced in NAFLD patients, independently from disease progression. In vitro, impaired LAL activity induced by FA loading was rescued by PPAR-alpha activation. These data suggest that the pharmacological modulation of LAL should be explored in the management of NAFLD patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of the epigenetic regulators in these processes remain largely elusive., Methods: Hepatocyte-specific Arid1a knockout mice were administrated with high-fat diet (HFD) for 12 weeks, then insulin sensitivity was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT). The metabolism-related indicators were determined by employing a variety of biological methods, including histology, real-time PCR, enzyme-linked immunosorbent assay (ELISA), Western blotting assay, Chromatin immunoprecipitation (ChIP), RNA-seq and assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq)., Findings: Hepatocyte-specific Arid1a deletion significantly increases susceptibility to develop hepatic steatosis, insulin resistance and inflammation in mice fed a HFD. In vitro, Arid1a deletion in isolated hepatocytes directly leads to free fatty acid-induced lipid accumulation and insulin resistance. Mechanically, Arid1a deficiency impairs fatty acid oxidation by downregulating PPARα and altering the epigenetic landscape of some metabolism genes., Interpretation: These findings reveal that targeting Arid1a might be a promising therapeutic strategy for liver steatosis and insulin resistance. FUND: This work was supported by National Natural Science Foundation of China (81672772 and 81472621), China National Science and Technology Major Project for Prevention and Treatment of Infectious Diseases (No.2017ZX 10203207) and National Program on Key Research Project of China (grant no. 2016YFC0902701)., (Copyright © 2019. Published by Elsevier B.V.)

The ability to detect changes in nutrient levels and generate an adequate response to these changes is essential for the proper functioning of living organisms. Adaptation to the high degree of variability in nutrient intake requires precise control of metabolic pathways. Mammals have developed different mechanisms to detect the abundance of nutrients such as sugars, lipids and amino acids and provide an integrated response. These mechanisms include the control of gene expression (from transcription to translation). This review reports the main molecular mechanisms that connect nutrients' levels, gene expression and metabolism in health. The manuscript is focused on sugars' signaling through the carbohydrate-responsive element binding protein (ChREBP), the role of peroxisome proliferator-activated receptors (PPARs) in the response to fat and GCN2/activating transcription factor 4 (ATF4) and mTORC1 pathways that sense amino acid concentrations. Frequently, alterations in these pathways underlie the onset of several metabolic pathologies such as obesity, insulin resistance, type 2 diabetes, cardiovascular diseases or cancer. In this context, the complete understanding of these mechanisms may improve our knowledge of metabolic diseases and may offer new therapeutic approaches based on nutritional interventions and individual genetic makeup.

Peroxisome proliferator-activated receptors (PPARs) are multi-domains proteins, belonging to the superfamily of nuclear receptors, which mainly act as ligand-activated transcription factors. A variety of lipophilic molecules, including long-chain polyunsaturated fatty acids and eicosanoids, are capable of binding to PPAR, although the nature of the physiological ligands is still under debate. PPARs regulate the expression of a set of genes involved in glucose and lipid metabolism as well as in the control of inflammatory responses. Herein we review the main molecular and cellular events associated with the activation of PPARs and their effects on metabolism.

Polar cod is an abundant Arctic key species, inhabiting an ecosystem that is subjected to rapid climate change and increased petroleum related activities. Few studies have investigated biological effects of crude oil on lipid metabolism in this species, despite lipids being a crucial compound for Arctic species to adapt to the high seasonality in food abundance in their habitat. This study examines the effects of dietary crude oil exposure on transcription levels of genes related to lipid metabolism (peroxisome proliferator-activated receptors [ppar-α, ppar-γ], retinoic X receptor [rxr-β], palmitoyl-CoA oxidase [aox1], cytochrome P4507A1 [cyp7α1]), reproduction (vitellogenin [vtg-β], gonad aromatase [cyp19a1]) and biotransformation (cytochrome P4501A1 [cyp1a1], aryl hydrocarbon receptor [ahr2]). Exposure effects were also examined through plasma chemistry parameters. Additional fish were exposed to a PPAR-α agonist (WY-14,643) to investigate the role of PPAR-α in their lipid metabolism. The dose-dependent up-regulation of cyp1a1 reflected the activation of genes related to PAH biotransformation upon crude oil exposure. The crude oil exposure did not significantly alter the mRNA expression of genes involved in lipid homeostasis except for cyp7α1 transcription levels. Plasma levels of cholesterol and alanine transaminase showed significant alterations in fish exposed to crude oil at the end of the experiment. WY exposure induced a down-regulation of ppar-α, an effect contrary to studies performed on other fish species. In conclusion, this study showed clear effects of dietary crude oil exposure at environmentally relevant concentrations on xenobiotic biotransformation but revealed only weak alterations in the lipid metabolism of polar cod., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The annual cycle of a migrating bird involves metabolically distinct stages of substantial fatty acid storage and periods of increased fatty acid mobilization and utilization, and thus requires a great deal of phenotypic flexibility. Specific mechanisms directing stage transitions of lipid metabolism in migrants are largely unknown. This study characterized the role of the PPARs (peroxisome proliferator-activated receptors) in regulating migratory adiposity of the gray catbird (Dumetella carolinensis). Catbirds increased adipose storage during spring and autumn migration and showed increased rates of basal lipolysis during migration and tropical overwintering. Expression of the PPAR target genes involved in fat uptake and storage, FABPpm and PLIN3, increased during pre-migratory fattening. We found significant correlation between PPARγ and target gene expression in adipose but little evidence that PPARα expression levels drive metabolic regulation in liver during the migratory cycle., (© 2016. Published by The Company of Biologists Ltd.)

Tinospora cordifolia (Guduchi Sawras) though has been clearly demonstrated in literature for its hypolipidemic and anti-alcoholism properties but its anti-hyperlipidemia mechanistic approach is still missing. Moreover, its direct implication with alcohol induced hyperlipidemia has also not been reported till date. In order to explore the answers of these questions, phytochemicals of Tinospora cordifolia water extract "Guduchi Sawras" (GS) was analyzed using HPLC-Q-TOF-MS. On the basis of relative peak volumes 110 compounds were selected and identified in GS. Besides that, protein targets of most abundant compounds present in GS were fetched from ChEMBL and protein interaction network (PIN) was constructed. GO enrichment analysis showed that GS targets various pathways including dopamine metabolism, cAMP-dependent signaling pathway, and glycolytic process. Biological processes obtained via PIN were correlated with hyperlipidemia markers and dopamine metabolism in moderate alcohol consumers (n=25) and healthy volunteers (n=27) of age 41±3.8years. Metabolic analysis demonstrated the increased serotonin (1.9-fold) and decreased dopamine (-2.3-fold) levels in alcoholics. Further data analysis revealed a significant increase in urinary BCAAs (>2.0-fold), pantothenic acid (1.8-fold), carnitines (>2-fold) levels, and decrease in PPARα activation markers levels i.e. nicotinamide-1-oxide (-1.7-fold), and N-methylnicotinamide (-1.6-fold) in alcoholics. Biochemical analysis showed the increased AST/ALT ratio (1.91), along with triglycerides (20%), and MDA (34%) and GSH (56%) levels in alcoholics. GS treatment significantly reverted the most of the discussed metabolites levels (p<0.05) and enzymes activities (p<0.05) in alcoholics. The data depict that moderate chronic alcohol consumption lead to hyperlipidemia and oxidative burden; whereas GS treatment ameliorates hyperlipidemia by decreasing oxidative stress, activating PPARα, CREB and SREBP-1 through stimulation of dopamine D1 receptors mediated signalling molecules i.e. cAMP and protein kinase A., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objective(s): Obesity leads to severe health issues like cardiovascular disease. Natural substances with anti-obesity properties are gaining attention. This study investigates the impact of taurine on lipid levels in rats fed a high-fat diet. Materials and Methods: The SD rats were fed a high-fat diet and treated with or without taurine for 21 weeks. Taurine was added to their drinking water, and an adipose triglyceride lipase (ATGL) inhibitor was injected for one week. The study evaluated the impact of taurine supplementation on the rats' body weight, Lee index, body fat content, serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), fatty acid synthase (FAS), ATGL, and peroxisome proliferator-activated receptor α (PPARα) in the liver. Fat accumulation in the liver and aortic arch was assessed through histopathological observations. Results: The study found that taurine reduced body weight, body fat, serum TG, TC, LDL-C levels, and lipid deposition in the liver and aortic arch while increasing serum HDL-C levels. Taurine intake also increased FAS and ATGL expression in the liver. Interestingly, the ATGL inhibitor atglistatin did not affect FAS and ATGL expression in the presence of taurine. Conclusion: Taurine can reduce fat deposition caused by a high-fat diet in SD rats by decreasing FAS content and increasing ATGL content. However, taurine does not fully regulate FAS and ATGL expression through the ATGL pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study aimed to elucidate the mechanism of oleuropein (OLE) ameliorates non‐alcoholic fatty liver disease (NAFLD) and its underlying mechanisms. RESULTS: Male C57BL/6J mice were fed either a low‐fat diet (LFD), a high‐fat diet (HFD), or a HFD supplemented with 0.03% (w/w) OLE for 16 weeks. OLE supplementation decreased body weight and liver weight, improved serum lipid profiles, and ameliorated HFD‐induced hepatic dysfunction. Liver metabolomics analysis revealed that OLE increased the levels of nicotinamide, tauroursodeoxycholic acid, taurine, and docosahexaenoic acid, which were beneficial for lipid homeostasis and inflammation regulation. OLE exerted its protective effects by activating peroxisome proliferator‐activated receptor alpha (PPARα), a key transcription factor that regulates fibroblast growth factor 21 (FGF21) expression and modulates lipid oxidation, lipogenesis and inflammation pathways. Importantly, OLE supplementation did not significantly affect body weight or liver weight in PPARα knockout (PPARα KO) mice, indicating that PPARα is essential for OLE‐mediated NAFLD prevention. CONCLUSION: Our results suggest that OLE alleviates NAFLD in mice by activating PPARα and modulating liver metabolites. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal–mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases. [ABSTRACT FROM AUTHOR]

The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia, and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increase susceptibility to oxidative stress, lipotoxicity, and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions and of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis, and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a cluster of clinical syndromes with diverse etiologies that ultimately result in a swift decline in kidney function. Regrettably, AKI lacks effective therapeutic agents at present. Neferine, a bioactive alkaloid derived from Lotus Plumule, has been reported to alleviate AKI triggered by cisplatin, ischemia/reperfusion (I/R), and sepsis by inhibiting inflammatory pathways. However, the precise molecular mechanisms underpinning its renoprotective effects remain elusive. Peroxisome proliferator-activated receptor alpha (PPAR-α), a regulator of lipid metabolism with anti-inflammatory properties, was investigated in this study to examine its role in neferine's renoprotective effects in cellular and mouse models of AKI. We found that neferine pretreatment in both I/R- or lipopolysaccharide (LPS)-induced AKI models inhibited the activation of the NF-κB inflammatory pathway and reversed PPAR-α deficiency. In NRK-52E cells exposed to hypoxia/reoxygenation (H/R) or LPS, overexpression of PPAR-α resulted in inhibition of the NF-κB pathway and TNF-α production, while PPAR-α silencing via siRNA transfection negated neferine's anti-inflammatory effects. Furthermore, pretreatment with neferine not only reduced lipid accumulation but also reversed the downregulation of FAO-related enzymes induced by LPS. Our findings suggest that neferine's renoprotective effects against AKI are partially mediated through the reversal of renal PPAR-α deficiency and subsequent inhibition of the inflammatory NF-κB pathway. Therefore, regulating renal PPAR-α expression by neferine could represent a promising therapeutic strategy for AKI. [ABSTRACT FROM AUTHOR]

This study investigated the antiobesity effects of black ginger extract (BGE) in high-fat diet (HFD)-induced obese mice. Mice were divided into six groups: normal diet control (NC, AIN-93G normal diet), 60% HFD control (HFD), HFD containing metformin at 250 mg/kg b.w. (Met, positive control), and HFD containing BGE at 5, 10, or 20 mg/kg b.w. for 15 weeks. BGE administration significantly prevented HFD-induced increases in weight gain, organ weight, and adipose tissue mass. Furthermore, it resulted in decreased adipogenesis and lipogenesis-related factors, including phosphorylated mitogen-activated protein kinase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins, sterol regulatory element-binding protein 1, phosphorylated cAMP response element-binding protein, glucose-6-phosphate dehydrogenase, fatty acid synthase, dephosphorylated ATP-citrate lyase, dephosphorylated acetyl-CoA carboxylase, and lipoprotein lipase, in white adipose tissues. Moreover, BGE administration enhanced lipolysis in white adipose tissue, as evidenced by elevated levels of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and protein kinase A, along with reduced levels of perilipin and phosphodiesterase 3B. BGE induced thermogenesis in brown adipose tissues, as reflected by the increased expression of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1 and decreased levels of fatty acid-binding protein 4. In conclusion, this study provides comprehensive evidence supporting the antiobesity effects of BGE, elucidating the underlying molecular mechanisms involved in preventing weight gain, suppressing adipogenesis, promoting lipolysis, and stimulating thermogenesis. These findings suggest the potential therapeutic utility of BGE in combating obesity and associated metabolic disorders (KHGASP-2023-034). [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress–induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress–induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress–inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study—lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. Key messages: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice. [ABSTRACT FROM AUTHOR]

Background: Sargentodoxae Caulis (SC) is the vine stem of Sargentodoxa Cuneata (Oliv.) Rehd. & E. H. Wilson in C. S. Sargent, and it in traditional Chinese medicine has been known for promoting blood circulation and removing blood stasis as recorded in the ancient book "Illustrated Classics of Materia Medica". It has been used effectively to treat blood stasis too in modern clinical practice. However, the anti-hyperlipidemia effect of SC is not fully understood. This paper aims at exploring the use of SC stems to improve the balance of blood lipids in the body, and its new role in treating hyperlipidemia. Methods: The effects of SC extract on hyperlipidemia were explored by combining lipidomics and gut microbiota. Secondly, we explored the potential mechanism of SC in treating hyperlipidemia by pathway analysis. Results: The results showed that the stem extract of SC could restore the physiological and biochemical indices of hyperlipidemia in mice, as well as repair the morphological and structural damage to tissues. Compared to the Model group, the SC extract significantly reduced the liver index, epididymal fat index, and Lee's index. It also significantly decreased serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, peroxisome proliferator-activated receptor gamma (PPAR-y), D-lactate, and free fatty acids, while significantly increasing the relative content of peroxisome proliferator-activated receptor alpha (PPAR-a). These changes were statistically significant. Non-targeted lipidomics, based on LC-MS, were utilized to investigate the lipid metabolism characteristics in serum, liver, and epididymal fat of the subjects. It was observed that, compared to the blank group, the Model group exhibited significant changes primarily in glycerol lipids and glycerophospholipids. The treatment group also displayed alterations in these lipids. A total of 38, 81, and 27 differential lipids were identified in serum, liver, and epididymal fat samples, respectively. Among these, 14 common differential lipids were found in both serum and liver samples, and their KEGG enrichment pathways were largely consistent. Among them, the sphingolipid signaling pathway and the glycerophospholipid metabolic pathway were identified as key metabolic pathways that were regulated. Our gut microbiota analysis revealed that SC diminishes the abundance of Actinobacteria by altering the cecal flora in mice. Conclusion: This alteration leads to the downregulation of genes involved in triglyceride metabolism, which in turn changes lipid processing and reduces triglyceride levels. Consequently, SC effectively combats hyperlipidemia. Notably, SC impacts key metabolic pathways, including the sphingolipid signaling and glycerophospholipid metabolism. These findings underscore SC's therapeutic potential, positioning it as a promising alternative for reducing the health risks associated with hyperlipidemia. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is increasingly recognized as being intertwined with the dysregulation of lipid metabolism. Lipids are a significant class of nutrients vital to all organisms, playing crucial roles in cellular structure, energy storage, and signaling. Alterations in the levels of various lipids in AD brains and dysregulation of lipid pathways and transportation have been implicated in AD pathogenesis. Clinically, evidence for a high-fat diet firmly links disrupted lipid metabolism to the pathogenesis and progression of AD, although contradictory findings warrant further exploration. In view of the significance of various lipids in brain physiology, the discovery of complex and diverse mechanisms that connect lipid metabolism with AD-related pathophysiology will bring new hope for patients with AD, underscoring the importance of lipid metabolism in AD pathophysiology, and promising targets for therapeutic intervention. Specifically, cholesterol, sphingolipids, and fatty acids have been shown to influence amyloid-beta (Ab) accumulation and tau hyperphosphorylation, which are hallmarks of AD pathology. Recent studies have highlighted the potential therapeutic targets within lipid metabolism, such as enhancing apolipoprotein E lipidation, activating liver X receptors and retinoid X receptors, and modulating peroxisome proliferator-activated receptors. Ongoing clinical trials are investigating the efficacy of these strategies, including the use of ketogenic diets, statin therapy, and novel compounds like NE3107. The implications of these findings suggest that targeting lipid metabolism could offer new avenues for the treatment and management of AD. By concentrating on alterations in lipid metabolism within the central nervous system and their contribution to AD development, this review aims to shed light on novel research directions and treatment approaches for combating AD, offering hope for the development of more effective management strategies. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the differentially expressed genes associated with intramuscular fat deposition in the longissimus dorsi muscle of Xinjiang Brown Bulls. The longissimus dorsi muscles of 10 Xinjiang Brown Bulls were selected under the same feeding conditions. The intramuscular fat content of muscle samples was determined by the Soxhlet extraction method, for which 5 samples with high intramuscular fat content (HIMF group) and 5 samples with low intramuscular fat content (LIMF group) were selected. It was found that the intramuscular fat content of the HIMF group was 46.054% higher than that of the LIMF group. Muscle samples produced by paraffin sectioning were selected for morphological observation. It was found that the fat richness of the HIMF group was better than that of the LIMF group. Transcriptome sequencing technology was used to analyze the gene expression differences of longissimus dorsi muscle. Through in-depth analysis of the longissimus dorsi muscle by transcriptome sequencing technology, we screened a total of 165 differentially expressed genes. The results of Gene Ontology (GO) enrichment analysis showed that the differentially expressed genes in the two groups were mainly clustered in biological pathways related to carbohydrate metabolic processes, redox processes and oxidoreductase activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes were significantly clustered in 15 metabolic pathways, which mainly covered fatty acid metabolism (related to lipid metabolism and glucose metabolism), the pentose phosphate pathway, the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and other important metabolic processes. The three genes that were predominantly enriched in the glycolipid metabolic pathway by analysis were SCD5, CPT1C and FBP2, all of which directly or indirectly affect intramuscular fat deposition. In summary, the present study investigated the differences in gene expression between high and low intramuscular fat content in the longissimus dorsi muscle of Xinjiang Brown Bulls by transcriptome sequencing technology and revealed the related signaling pathways. Therefore, we hypothesized that SCD5, CPT1C and FBP2 were the key genes responsible for the significant differences in intramuscular fat content of the longissimus dorsi muscles in a population of Xinjiang Brown Bulls. We expect that these findings will provide fundamental support for subsequent studies exploring key genes affecting fat deposition characteristics in Xinjiang Brown Bulls. [ABSTRACT FROM AUTHOR]

Aims As the interactions of alcohol and HIV/SIV infection and their impact on liver metabolic homeostasis remain to be fully elucidated, this study aimed to determine alcohol-mediated hepatic adaptations of metabolic pathways in SIV/ART-treated female rhesus macaques fed a nutritionally balanced diet. Methods Macaques were administered chronic binge alcohol (CBA; 13–14 g ethanol/kg/week for 14.5 months; n = 7) or vehicle (VEH; n = 8) for 14.5 months. Livers were excised following an overnight fast. Gene and protein expression, enzymatic activity, and lipid content were determined using frozen tissue and histological staining was performed using paraffin-embedded tissue. Results CBA/SIV macaques showed increased hepatic protein expression of electron transport Complex III and increased gene expression of glycolytic (phosphofructokinase and aldolase) and gluconeogenic (pyruvate carboxylase) enzymes and of genes involved in lipid turnover homeostasis (perilipin 1, peroxisome proliferator-activated receptor gamma, carbohydrate responsive binding protein, and acetyl-CoA carboxylase B) as compared to that of livers from the VEH/SIV group. Plasma triglyceride concentration had a significant positive association with liver triglyceride content in the CBA/SIV group. Conclusions These results reflect CBA-associated alterations in expression of proteins and genes involved in glucose and lipid metabolism homeostasis without significant evidence of steatosis or dysglycemia. Whether these changes predispose to greater liver pathology upon consumption of a high fat/high sugar diet that is more aligned with dietary intake of PWH and/or exposure to additional environmental factors warrants further investigation. [ABSTRACT FROM AUTHOR]

Excessive fat deposition leads to obesity and cardiovascular diseases with abnormal metabolism. Pantothenic acid (PA) is a major B vitamin required for energy metabolism. However, the effect of PA on lipid metabolism and obesity has not been explored. We investigated the effects and molecular mechanism of PA on fat accumulation as well as the influence of adipogenic marker genes in both adult male mice and primary adipocytes. First, we demonstrated that PA attenuates weight gain in mice fed high-fat diet (HFD). Besides, PA supplementation substantially improved glucose tolerance and lipid metabolic disorder in obese mice. Furthermore, PA significantly inhibited white adipose tissue (WAT) deposition as well as fat droplets visualized by magnification in both chow and HFD group. More importantly, PA obviously suppressed the mRNA levels of CD36, IL-6, and TNF-α to alleviate inflammation and reduced the levels of PPARγ, aP2, and C/EBPα genes that are related to lipid metabolism in inguinal white adipose tissue (ing-WAT) and epididymal white adipose tissue (ei-WAT). In vitro, PA supplementation showed a lower lipid droplet aggregation as well as reduced expression levels of adipogentic genes. Finally, we identified that PA inhibits the phosphorylation levels of p38 and JNK in murine primary adipocytes. Collectively, our data demonstrated for the first time that PA attenuates lipid metabolic disorder as well as fat deposition by JNK/p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, cancer has gradually become a terrible killer of human health. Due to various factors such as tumor heterogeneity and the complexity of the microenvironment, completely conquering cancer has always been a major problem in the scientific research community. Therefore, more detailed research and individualized treatment are essential. Everyone knows that tumor cells in the process of rapid proliferation need replenishing nutrients to sustain their energy supply. Intervention of tumor cell metabolism is gradually becoming a way to treat cancer. As an important transporter of glutamine, ASCT2 can uptake glutamine from the tumor microenvironment to support the growth and metabolism of cancer cells. Deficiency of ASCT2 can significantly inhibit tumor progression. However, not all patients benefit from this treatment. Our study aims to explore the metabolic heterogeneity of breast cancer and its related mechanisms, as well as to find metabolic-sensitive populations for further precision treatment. As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine–lipid feedback loop. [ABSTRACT FROM AUTHOR]

The most prevalent chronic liver disease, known as metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by an excessive accumulation of lipids and oxidative damage. Clinopodium gracile, a natural herbal medicine widely used by Chinese folk, has antioxidative, anti-inflammatory, and lipid metabolism-regulating effects. Here, we explored the effect of C. gracile extract (CGE) on MASLD using palmitic acid (PA)-induced hepatocytes and high-fat diet (HFD)-fed mice. In vitro, CGE could promote fatty acid oxidation and inhibit fatty acid synthesis and uptake to reduce lipid accumulation by regulating PPARα activation. Moreover, CGE could inhibit reactive oxygen species production and maintain mitochondrial homeostasis in PA-induced HepG2 cells. In vivo, animal study results indicated that CGE could effectively reduce lipid metabolism disorder, inhibit oxidative stress, and upregulate PPARα protein in the liver of HFD-fed mice. Molecular docking results also showed that active compounds isolated from CGE had low binding energy and highly stable binding with PPARα. In summary, these findings reveal that CGE may be a potential therapeutic candidate for MASLD and act by upregulating PPARα to reduce lipid accumulation and suppress mitochondrial oxidative damage. [ABSTRACT FROM AUTHOR]

Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy. [ABSTRACT FROM AUTHOR]

Background: The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients. Methods: Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. Results: To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis. Conclusions: We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

Objective: This research aims to explore how Puerariae Lobatae Radix regulates sebaceous gland secretion using network pharmacology, and validate its effects on important targets through animal studies. Methods: This study utilized UPLC-EQ-MS to analyze Puerariae Lobatae Radix extract and identify potential bioactive compounds. Predicted targets of these compounds were obtained from the Swiss Target Prediction database, while targets associated with sebaceous gland secretion were obtained from the GeneCards database. Common targets between the databases were identified and a protein-protein interaction (PPI) network was established using the STRING platform. The PPI network was further analyzed using Cytoscape software. Pathway enrichment analysis was performed using Reactome, and molecular docking experiments targeted pivotal pathway proteins. Animal experiments were then conducted to validate the regulatory effects of the primary active compounds of Puerariae Lobatae Radix on key pathway proteins. Results: This research identified 17 active compounds in Puerariae Lobatae Radix and 163 potential targets associated with the regulation of sebum secretion. Pathway enrichment analysis indicates that these targets may modulate lipid metabolism pathways through involvement in peroxisome proliferator-activated receptor α, SREB, steroid metabolism, and arachidonic acid metabolism pathways. Molecular docking analysis demonstrates that puerarin and daidzein show favorable binding interactions with key targets in these pathways. Animal experiments demonstrated that the administration of Puerariae Lobatae Radix resulted in a significant reduction in the area of sebaceous gland patches compared to the control group. Histological analysis revealed notable alterations in the structure of sebaceous glands, including reductions in size, thickness, and density. Furthermore, the expression levels of TG, DHT, and IL-6 were significantly decreased in the Puerariae Lobatae Radix group (p < 0.05), and immunoblotting indicated a significant decrease in the expression of PPARG and ACC1 (p < 0.05). Conclusion: This study demonstrates that Puerariae Lobatae Radix can regulate skin lipid metabolism by targeting multiple pathways. The primary mechanism involves inhibiting sebaceous gland growth and reducing TG secretion by modulating the expression of PPARG and ACC1. Puerarin and Daidzein are identified as key bioactive compounds responsible for this regulatory effect. These findings highlight the therapeutic potential of Puerariae Lobatae Radix in addressing sebaceous gland-related conditions. [ABSTRACT FROM AUTHOR]

Background: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is higher in men than in women. Hormonal and genetic causes may account for the sex differences in MASLD. Current human in vitro liver models do not sufficiently take the influence of biological sex and sex hormones into consideration. Methods: Primary human hepatocytes (PHHs) were isolated from liver specimen of female and male donors and cultured with sex hormones (17β-estradiol, testosterone and progesterone) for up to 72 h. mRNA expression levels of 8 hepatic lipid metabolism genes were analyzed by RT-qPCR. Sex hormones and their metabolites were determined in cell culture supernatants by LC-MS analyses. Results: A sex-specific expression was observed for LDLR (low density lipoprotein receptor) with higher mRNA levels in male than female PHHs. All three sex hormones were metabolized by PHHs and the effects of hormones on gene expression levels varied depending on hepatocyte sex. Only in female PHHs, 17β-estradiol treatment affected expression levels of PPARA (peroxisome proliferator-activated receptor alpha), LIPC (hepatic lipase) and APOL2 (apolipoprotein L2). Further changes in mRNA levels of female PHHs were observed for ABCA1 (ATP-binding cassette, sub-family A, member 1) after testosterone and for ABCA1, APOA5 (apolipoprotein A-V) and PPARA after progesterone treatment. Only the male PHHs showed changing mRNA levels for LDLR after 17β-estradiol and for APOA5 after testosterone treatment. Conclusions: Male and female PHHs showed differences in their expression levels of hepatic lipid metabolism genes and their responsiveness towards sex hormones. Thus, cellular sex should be considered, especially when investigating the pathophysiological mechanisms of MASLD. [ABSTRACT FROM AUTHOR]

A subgroup of endocrine‐disrupting chemicals have the ability to disrupt metabolism. These metabolism‐disrupting chemicals (MDCs) can end up in aquatic environments and lead to adverse outcomes in fish. Although molecular and physiological effects of MDCs have been studied in adult fish, few studies have investigated the consequences of metabolic disruption in fish during the earliest life stages. To investigate the processes affected by metabolic disruption, zebrafish embryos were exposed to peroxisome proliferator–activated receptor gamma (PPARγ) agonist rosiglitazone, the PPARγ antagonist T0070907, and the well‐known environmentally relevant MDC bisphenol A. Decreased apolipoprotein Ea transcript levels indicated disrupted lipid transport, which was likely related to the observed dose‐dependent increases in yolk size across all compounds. Increased yolk size and decreased swimming activity indicate decreased energy usage, which could lead to adverse outcomes because the availability of energy reserves is essential for embryo survival and growth. Exposure to T0070907 resulted in a darkened yolk. This was likely related to reduced transcript levels of genes involved in lipid transport and fatty acid oxidation, a combination of responses that was specific to exposure to this compound, possibly leading to lipid accumulation and cell death in the yolk. Paraoxonase 1 (Pon1) transcript levels were increased by rosiglitazone and T0070907, but this was not reflected in PON1 enzyme activities. The present study shows how exposure to MDCs can influence biochemical and molecular processes involved in early lipid metabolism and may lead to adverse outcomes in the earliest life stages of fish. Environ Toxicol Chem 2024;43:1880–1893. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is an aging-associated interstitial lung disease resulting from repeated epithelial injury and inadequate epithelial repair. Alveolar type II cells (AEC2s) are progenitor cells that maintain epithelial homeostasis and repair the lung after injury. In the current study, we assessed lipid metabolism in AEC2s from human lungs of patients with IPF and healthy donors, as well as AEC2s from bleomycin-injured young and old mice. Through single-cell RNA sequencing, we observed that lipid metabolism–related genes were downregulated in IPF AEC2s and bleomycin-injured mouse AEC2s. Aging aggravated this decrease and hindered recovery of lipid metabolism gene expression in AEC2s after bleomycin injury. Pathway analyses revealed downregulation of genes related to lipid biosynthesis and fatty acid β-oxidation in AEC2s from IPF lungs and bleomycin-injured, old mouse lungs compared with the respective controls. We confirmed decreased cellular lipid content in AEC2s from IPF lungs and bleomycin-injured, old mouse lungs using immunofluorescence staining and flow cytometry. Futhermore, we show that lipid metabolism was associated with AEC2 progenitor function. Lipid supplementation and PPARγ (peroxisome proliferator activated receptor γ) activation promoted progenitor renewal capacity of both human and mouse AEC2s in three-dimensional organoid cultures. Lipid supplementation also increased AEC2 proliferation and expression of SFTPC in AEC2s. In summary, we identified a lipid metabolism deficiency in AEC2s from lungs of patients with IPF and bleomycin-injured old mice. Restoration of lipid metabolism homeostasis in AEC2s might promote AEC2 progenitor function and offer new opportunities for therapeutic approaches to IPF. [ABSTRACT FROM AUTHOR]

Introduction: Pueraria lobata is traditionally used in China for treatment of nonalcoholic fatty liver disease (NAFLD). Puerarin, a functional drug extracted from Pueraria lobata, features a pharmacological activity. The present study aims to investigate the effect of puerarin intervention on NAFLD. Methods: We established an NAFLD mouse model using a high-fat diet with 60% fat and evaluated the impact of puerarin intervention. Results and discussion: Our results demonstrate that puerarin intervention significantly ameliorates lipid accumulation and protects the liver from highfat-induced damage while reducing oxidative stress levels in the liver. Furthermore, puerarin intervention significantly downregulates the transcription levels of acetyl-CoA carboxylase (ACC1) in the liver. It also upregulates the transcription levels of carnitine palmitoyltransferase 1 (CPT1), peroxisome proliferator-activated receptor alpha (PPARα), and peroxisome proliferators-activated receptor γ coactivator alpha (PGC1α), which are related to oxidation. Furthermore, we demonstrated that flavin-containing monooxygenase (FMO5) was involved in the protective effect of puerarin against NFALD. In conclusion, the present study demonstrated the beneficial effect of puerarin on NAFLD and showed that puerarin could prevent liver injury and lipid accumulation caused by NAFLD via activating FMO5. These findings provide a new theoretical basis for applying puerarin as a therapeutic agent for NAFLD. [ABSTRACT FROM AUTHOR]

The binding of peroxisome proliferator‐activated receptor γ (PPARγ) to the orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant fatty acid uptake for breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti‐breast‐cancer therapy. However, developing an inhibitor of the Nur77‐PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST‐CY14, a stapled peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10−8 M by in silico analysis, rational design, and structural modification. ST‐CY14 effectively increases Nur77 protein levels by blocking the Nur77‐PPARγ interaction, thereby inhibiting lipid metabolism in breast tumor cells. Notably, ST‐CY14 significantly suppresses breast cancer growth and bone metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77‐PPARγ interaction in breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77‐PPARγ interaction available for impeding fatty acid uptake and therapeutic development. [ABSTRACT FROM AUTHOR]

Acylglycerophosphate acyltransferases (AGPATs) catalyze the de novo formation of phosphatidic acid to synthesize glycerophospholipids and triglycerides. AGPATs demonstrate unique physiological roles despite a similar biochemical function. AGPAT3 is highly expressed in the testis, kidney, and liver, with intermediate expression in adipose tissue. Loss of AGPAT3 is associated with reproductive abnormalities and visual dysfunction. However, the role of AGPAT3 in adipose tissue and whole body metabolism has not been investigated. We found that male Agpat3 knockout (KO) mice exhibited reduced body weights with decreased white and brown adipose tissue mass. Such changes were less pronounced in the female Agpat3-KO mice. Agpat3-KO mice have reduced plasma insulin growth factor 1 (IGF1) and insulin levels and diminished circulating lipid metabolites. They manifested intact glucose homeostasis and insulin sensitivity despite a lean phenotype. Agpat3-KO mice maintained an energy balance with normal food intake, energy expenditure, and physical activity, except for increased water intake. Their adaptive thermogenesis was also normal despite reduced brown adipose mass and triglyceride content. Mechanistically, Agpat3 was elevated during mouse and human adipogenesis and enriched in adipocytes. Agpat3-knockdown 3T3-L1 cells and Agpat3-deficient mouse embryonic fibroblasts (MEFs) have impaired adipogenesis in vitro. Interestingly, pioglitazone treatment rescued the adipogenic deficiency in Agpat3-deficient cells. We conclude that AGPAT3 regulates adipogenesis and adipose development. It is possible that adipogenic impairment in Agpat3-deficient cells potentially leads to reduced adipose mass. Findings from this work support the unique role of AGPAT3 in adipose tissue. NEW & NOTEWORTHY AGPAT3 deficiency results in male-specific growth retardation. It reduces adipose tissue mass but does not significantly impact glucose homeostasis or energy balance, except for influencing water intake in mice. Like AGPAT2, AGPAT3 is upregulated during adipogenesis, potentially by peroxisome proliferator-activated receptor gamma (PPARc). Loss of AGPAT3 impairs adipocyte differentiation, which could be rescued by pioglitazone. Overall, AGPAT3 plays a significant role in regulating adipose tissue mass, partially involving its influence on adipocyte differentiation. [ABSTRACT FROM AUTHOR]

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-a targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (Acadm, Acox1, Cpt2, Cyp4a1-3) and downregulation of lipid transport genes (Apoa1, Apoa5, Pltp). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis (Pck1) and bile acid synthesis (Cyp7a1) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis (Scd) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFASinduced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Body metabolism and colonic microbiota collectively controlled lipid metabolism in finishing pigs. Diminishing standardized ileal digestible lysine to net energy ratio in high-wheat diets may regulate lipid metabolism via AMP-activated protein kinase α1/sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator-1α pathway and farnesol X receptor/small heterodimer partner pathway, ultimately increased the marbling score of longissimus dorsi muscle. The present study aimed to investigate the impacts of dietary standardized ileal digestible lysine to net energy (SID Lys:NE) ratio on lipid metabolism in pigs fed high-wheat diets. Thirty-six crossbred growing barrows (65.20 ± 0.38 kg) were blocked into two treatment groups, fed high-wheat diets with either a high SID Lys:NE ratio (HR) or a low SID Lys:NE ratio (LR). Each treatment group consisted of three replicates, with six pigs per pen in each replicate. The diminishing dietary SID Lys:NE ratio exhibited no adverse impacts on the carcass trait (p > 0.05) but increased the marbling score of the longissimus dorsi muscle (p < 0.05). Meanwhile, LR diets tended to increase the serum triglyceride concentration (p < 0.1). LR diets upregulated fatty acid transport protein 4 and acetyl-coA carboxylase α expression levels and downregulated the expression level of adipose triglyceride lipase (p < 0.05). LR diets improved energy metabolism via decreasing the expression levels of AMP-activated protein kinase (AMPK) α1, sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) (p < 0.05). Additionally, LR diets stimulated hepatic bile acid synthesis via upregulating the expression levels of cytochrome P450 family 7 subfamily A member 1 and cytochrome P450 family 27 subfamily A member 1, and downregulating farnesol X receptor (FXR) and small heterodimer partner (SHP) expression levels (p < 0.05). A lowered SID Lys:NE ratio affected the colonic microbial composition, characterized by increased relative abundances of YRC22, Parabacteroides, Sphaerochaeta, and Bacteroides, alongside a decreased in the proportion of Roseburia, f_Lachnospiraceae_g_Clostridium, Enterococcus, Shuttleworthia, Exiguobacterium, Corynebacterium, Subdoligranulum, Sulfurospirillum, and Marinobacter (p < 0.05). The alterations in microbial composition were accompanied by a decrease in colonic butyrate concentration (p < 0.1). The metabolomic analysis revealed that LR diets affected primary bile acid synthesis and AMPK signaling pathway (p < 0.05). And the mantel analysis indicated that Parabacteroides, Sphaerochaeta, f_Lachnospiraceae_g_Clostridium, Shuttleworthia, and Marinobacter contributed to the alterations in body metabolism. A reduced dietary SID Lys:NE ratio improves energy metabolism, stimulates lipogenesis, and inhibits lipolysis in finishing pigs by regulating the AMPKα/SIRT1/PGC-1α pathway and the FXR/SHP pathway. Parabacteroides and Sphaerochaeta benefited bile acids synthesis, whereas f_Lachnospiraceae_g_Clostridium, Shuttleworthia, and Marinobacter may contribute to the activation of the AMPK signaling pathway. Overall, body metabolism and colonic microbiota collectively controlled the lipid metabolism in finishing pigs. [ABSTRACT FROM AUTHOR]

Asprosin (ASP) is a newly‐identified adipokine and plays important roles in energy metabolism homeostasis. However, there is no report on whether and how ASP is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Therefore, in the study, we investigated the protective effects of ASP‐deficiency on the liver in the NAFLD model mice and the detrimental effects of ASP treatment on the human normal hepatocytes (LO2 cell line). More important, we explored the underlying mechanism from the perspective of lipid metabolism and inflammation. In the in vivo experiments, our data showed that the ASP‐deficiency significantly alleviated the high‐fat diet‐induced inflammation and NAFLD, inhibited the hepatic fat deposition and downregulated the expressions of fat acid synthase (FASN), peroxisome proliferator‐activated receptor γ (PPARγ) and forkhead box protein O1 (FOXO1); moreover, the ASP‐deficiency attenuated the inflammatory state and inhibited the activation of the IKK/NF‐κBp65 inflammation pathway. In the in vitro experiments, our results revealed that ASP treatment caused and even exacerbated the injury of LO2 cells induced by FFA; In contrast, the ASP treatment upregulated the expressions of PPARγ, FOXO1, FASN, ACC and acyl‐CoA oxidase 1 (ACOX1) and elevated the reactive oxygen species (ROS) levels. Accordingly, these results demonstrate that ASP causes NAFLD through disrupting lipid metabolism and promoting the inflammation mediated by ROS. [ABSTRACT FROM AUTHOR]

Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is regulated by cells autonomously is unclear. In this study, we discovered that absence of the lipid regulator nhr-49, a functional ortholog of the peroxisome proliferator-activated receptor (PPAR) in Caenorhabditis elegans, resulted in defective pathogen avoidance behavior against Pseudomonas aeruginosa (PA14). Functional NHR-49 was required in the neurons, and more specifically, in a set of oxygen-sensing body cavity neurons, URX, AQR, and PQR. We found that lowering the neuronal activity of the body cavity neurons improved avoidance in nhr-49 mutants. Calcium imaging in URX neurons showed that nhr-49 mutants displayed longer-lasting calcium transients in response to an O2 upshift, suggesting that excess neuronal activity leads to avoidance defects. Cell-specific rescue of NHR-49 in the body cavity neurons was sufficient to improve pathogen avoidance, as well as URX neuron calcium kinetics. Supplementation with oleic acid also improved avoidance behavior and URX calcium kinetics, suggesting that the defective calcium response in the neuron is due to lipid dysfunction. These findings highlight the role of cell-autonomous lipid regulation in neuronal physiology and immune behavior. [ABSTRACT FROM AUTHOR]

Background: In addition to abnormal liver inflammation, the main symptoms of non-alcoholic steatohepatitis (NASH) are often accompanied by gastrointestinal digestive dysfunction, consistent with the concept of spleen deficiency (SD) in traditional Chinese medicine. As an important metabolic sensor, whether peroxisome proliferator-activated receptor alpha (PPARa) participates in regulating the occurrence and development of NASH with SD (NASH-SD) remains to be explored. Methods: Clinical liver samples were collected for RNA-seq analysis. C57BL/6J mice induced by folium sennae (SE) were used as an SD model. qPCR analysis was conducted to evaluate the inflammation and metabolic levels of mice. PPARa knockout mice (PPARako) were subjected to SE and methionine-choline-deficient (MCD) diet to establish the NASH-SD model. The phenotype of NASH and the inflammatory indicators were measured using histopathologic analysis and qPCR as well. Results: The abnormal expression of PPARa signaling, coupled with metabolism and inflammation, was found in the results of RNA-seq analysis from clinical samples. SD mice showed a more severe inflammatory response in the liver evidenced by the increases in macrophage biomarkers, inflammatory factors, and fibrotic indicators in the liver. qPCR results also showed differences in PPARa between SD mice and control mice. In PPARako mice, further evidence was found that the lack of PPARa exacerbated the inflammatory response phenotype as well as the lipid metabolism disorder in NASH-SD mice. Conclusion: The abnormal NR signaling accelerated the vicious cycle between lipotoxicity and inflammatory response in NAFLD with SD. Our results provide new evidence for nuclear receptors as potential therapeutic targets for NAFLD with spleen deficiency. [ABSTRACT FROM AUTHOR]

The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis. Hypertension, and organ system dysfunctions associated with preeclampsia (PE) result in poor pregnancy outcomes. In the current study, the authors examined molecular pathogenesis of PE with a focus Peroxisome proliferator-activated receptor gamma (PPARγ), lipid metabolism, and ferroptosis in the placenta of PE patients. [ABSTRACT FROM AUTHOR]

In steatotic liver diseases (SLDs), including metabolic dysfunction-associated SLD and alcohol-associated liver disease, the excessive hepatic metabolism of lipids and alcohol leads to an increase in hepatic mitochondrial reductive stress, which in turn contributes to the development of SLD. Recent genetic studies conducted on both humans and mice have provided further evidence highlighting the key role played by hepatic mitochondrial reductive stress in the pathogenesis of SLD. Several pharmaceutical agents currently in development for the treatment of SLD, such as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers, share an under-recognized common characteristic in that they decrease hepatic mitochondrial reductive stress. A more comprehensive understanding of hepatic mitochondrial reductive stress could help elucidate disease pathogenesis and facilitate the identification of new therapeutic approaches. Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress. This review aims to explore how these risk factors increase hepatic mitochondrial reductive stress and how it disrupts hepatic metabolism, leading to SLDs. Additionally, the review will discuss the latest clinical studies on pharmaceutical treatments for SLDs, specifically peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor (THR) agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers. These treatments have a common effect of decreasing hepatic mitochondrial reductive stress, which has been largely overlooked. [ABSTRACT FROM AUTHOR]

Background: This study was designed to evaluate the effects of low-frequency electroacupuncture (EA) on glucose and lipid disturbances in a rat model of polycystic ovary syndrome (PCOS) characterized by insulin resistance (IR) and hepatic steatosis. Methods: The PCOS rat model was induced by continuous administration of letrozole (LET) combined with a high-fat diet (HFD). Female Sprague–Dawley rats were divided into the following four groups: control, control + EA, LET + HFD and LET + HFD + EA. EA was administered five or six times a week with a maximum of 20 treatment sessions. Body weight, estrous cyclicity, hormonal status, glucose and insulin tolerance, lipid profiles, liver inflammation factors, liver morphology and changes in the phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway were evaluated. Results: The rat model presented anovulatory cycles, increased body weight, elevated testosterone, abnormal glucose and lipid metabolism, IR, liver inflammation, hepatic steatosis and dysregulation of the insulin-mediated PI3-K/Akt signaling axis. EA reduced fasting blood glucose, fasting insulin, area under the curve for glucose, homeostasis model assessment of IR indices, triglycerides and free fatty acids, and alleviated hepatic steatosis. Furthermore, low-frequency EA downregulated mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6, upregulated mRNA expression of peroxisome proliferator-activated receptor (PPAR)-α, increased protein expression of phosphorylated (p)-Akt (Ser473), p-glycogen synthase kinase (GSK) 3β (Ser9) and glucose transporter 4 (GLUT4), increased the ratio of p-GSK3β to GSK3β and downregulated protein expression of GSK3β. Conclusion: An obese PCOS rat model with IR and hepatic steatosis was successfully established by the combination of LET and HFD. EA improved dysfunctional glucose and lipid metabolism in this PCOS-IR rat model, and the molecular mechanism appeared to involve regulation of the expression of key molecules of the PI3-K/Akt insulin signaling pathway in the liver. [ABSTRACT FROM AUTHOR]

Objective: Psoralea corylifolia L. (FP) has received increasing attention due to its potential hepatotoxicity. Methods: In this study, zebrafish were treated with different concentrations of an aqueous extract of FP (AEFP; 40, 50, or 60 μg/mL), and the hepatotoxic effects of tonicity were determined by the mortality rate, liver morphology, fluorescence area and intensity of the liver, biochemical indices, and pathological tissue staining. The mRNA expression of target genes in the bile acid metabolic signaling pathway and lipid metabolic pathway was detected by qPCR, and the mechanism of toxicity was initially investigated. AEFP (50 μg/mL) was administered in combination with FXR or a peroxisome proliferator-activated receptor α (PPARα) agonist/inhibitor to further define the target of toxicity. Results: Experiments on toxic effects showed that, compared with no treatment, AEFP administration resulted in liver atrophy, a smaller fluorescence area in the liver, and a lower fluorescence intensity (p < 0.05); alanine transaminase (ALT), aspartate transaminase (AST), and γ-GT levels were significantly elevated in zebrafish (p < 0.01), and TBA, TBIL, total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were elevated to different degrees (p < 0.05); and increased lipid droplets in the liver appeared as fatty deposits. Molecular biological validation revealed that AEFP inhibited the expression of the FXR gene, causing an increase in the expression of the downstream genes SHP, CYP7A1, CYP8B1, BSEP, MRP2, NTCP, peroxisome proliferator-activated receptor γ (PPARγ), ME-1, SCD-1, lipoprotein lipase (LPL), CPT-1, and CPT-2 and a decrease in the expression of PPARα (p < 0.05). Conclusion: This study demonstrated that tonic acid extracts are hepatotoxic to zebrafish through the inhibition of FXR and PPARα expression, thereby causing bile acid and lipid metabolism disorders. [ABSTRACT FROM AUTHOR]

Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 μg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 μg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs. [ABSTRACT FROM AUTHOR]

Bile acids are synthesized from cholesterol in the liver. Dysregulation of bile acid homeostasis, characterized by excessive accumulation in the liver, gallbladder and blood, can lead to hepatocellular damage and the development of cholestatic liver disease. Nuclear receptors play a crucial role in the control of bile acid metabolism by efficiently regulating bile acid synthesis and transport in the liver. Among these receptors, peroxisome proliferator‐activated receptor (PPAR), a ligand‐activated transcription factor belonging to the nuclear hormone receptor superfamily, controls the expression of genes involved in adipogenesis, lipid metabolism, inflammation and glucose homeostasis and has emerged as a potential therapeutic target for the treatment of the metabolic syndrome in the past two decades. Emerging evidence suggests that PPAR activation holds promise as a therapeutic target for cholestatic liver disease, as it affects both bile acid production and transport. This review provides a comprehensive overview of recent advances in elucidating the role of PPAR in the regulation of bile acid metabolism, highlighting the current position of PPAR agonists in the treatment of primary biliary cholangitis. By summarizing the specific regulatory effects of PPAR on bile acids, this review contributes to the exploration of novel therapeutic strategies for cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

Phthalic acid esters (PAEs), commonly used as plasticizers, are pervasive in the environment, leading to widespread human exposure. The association between phthalate exposure and metabolic disorders has been increasingly recognized, yet the precise biological mechanisms are not well-defined. In this study, we explored the effects of monoethylhexyl phthalate (MEHP) and monocyclohexyl phthalate (MCHP) on glucose and lipid metabolism in human hepatocytes and adipocytes. In hepatocytes, MEHP and MCHP were observed to enhance lipid uptake and accumulation in a dose-responsive manner, along with upregulating genes involved in lipid biosynthesis. Transcriptomic analysis indicated a broader impact of MEHP on hepatic gene expression relative to MCHP, but MCHP particularly promoted the expression of the gluconeogenesis key enzymes G6PC and FBP1. In adipocytes, MEHP and MCHP both increased lipid droplet formation, mimicking the effects of the Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi). Transcriptomic analysis revealed that MEHP predominantly altered fatty acid metabolism pathways in mature adipocytes (MA), whereas MCHP exhibited less impact. Metabolic perturbations from MEHP and MCHP demonstrate shared activation of the PPARs pathway in hepatocytes and adipocytes, but the cell-type discrepancy might be attributed to the differential expression of PPARγ. Our results indicate that MEHP and MCHP disrupt glucose and lipid homeostasis in human liver and adipose through mechanisms that involve the PPAR and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways, highlighting the nuanced cellular responses to these environmental contaminants. [ABSTRACT FROM AUTHOR]

Physiologically, renal medullary cells are surrounded by a hyperosmolar interstitium. However, different pathological situations can induce abrupt changes in environmental osmolality, causing cell stress. Therefore, renal cells must adapt to survive in this new condition. We previously demonstrated that, among the mechanisms involved in osmoprotection, renal cells upregulate triglyceride biosynthesis (which helps preserve glycerophospholipid synthesis and membrane homeostasis) and cyclooxygenase‐2 (which generates prostaglandins from arachidonic acid) to maintain lipid metabolism in renal tissue. Herein, we evaluated whether hyperosmolality modulates phospholipase A2 (PLA2) activity, leading to arachidonic acid release from membrane glycerophospholipid, and investigated its possible role in hyperosmolality‐induced triglyceride synthesis and accumulation. We found that hyperosmolality induced PLA2 expression and activity in Madin‐Darby canine kidney cells. Cytosolic PLA2 (cPLA2) inhibition, but not secreted or calcium‐independent PLA2 (sPLA2 or iPLA2, respectively), prevented triglyceride synthesis and reduced cell survival. Inhibition of prostaglandin synthesis with indomethacin not only failed to prevent hyperosmolality‐induced triglyceride synthesis but also exacerbated it. Similar results were observed with the peroxisomal proliferator activated receptor gamma (PPARγ) agonist rosiglitazone. Furthermore, hyperosmolality increased free intracellular arachidonic acid levels, which were even higher when prostaglandin synthesis was inhibited by indomethacin. Blocking PPARγ with GW‐9662 prevented the effects of both indomethacin and rosiglitazone on triglyceride synthesis and even reduced hyperosmolality‐induced triglyceride synthesis, suggesting that arachidonic acid may stimulate triglyceride synthesis through PPARγ activation. These results highlight the role of cPLA2 in osmoprotection, since it is essential to provide arachidonic acid, which is involved in PPARγ‐regulated triglyceride synthesis, thus guaranteeing cell survival. [ABSTRACT FROM AUTHOR]

This study aims to use spatial transcriptomics to characterize the cell-type-specific expression profile associated with the microscopic features observed in Wooden Breast myopathy. 1 cm3 muscle sample was dissected from the cranial part of the right pectoralis major muscle from three randomly sampled broiler chickens at 23 days post-hatch and processed with Visium Spatial Gene Expression kits (10X Genomics), followed by high-resolution imaging and sequencing on the Illumina Nextseq 2000 system. WB classification was based on histopathologic features identified. Sequence reads were aligned to the chicken reference genome (Galgal6) and mapped to histological images. Unsupervised K-means clustering and Seurat integrative analysis differentiated histologic features and their specific gene expression pattern, including lipid laden macrophages (LLM), unaffected myofibers, myositis and vasculature. In particular, LLM exhibited reprogramming of lipid metabolism with up-regulated lipid transporters and genes in peroxisome proliferator-activated receptors pathway, possibly through P. Moreover, overexpression of fatty acid binding protein 5 could enhance fatty acid uptake in adjacent veins. In myositis regions, increased expression of cathepsins may play a role in muscle homeostasis and repair by mediating lysosomal activity and apoptosis. A better knowledge of different cell-type interactions at early stages of WB is essential in developing a comprehensive understanding. [ABSTRACT FROM AUTHOR]

Obesity and metabolic disorders caused by alterations in lipid metabolism are major health issues in developed, affluent societies. Adipose tissue is the only organ that stores lipids and prevents lipotoxicity in other organs. Mature adipocytes can affect themselves and distant metabolism‐related tissues by producing various adipokines, including adiponectin and leptin. The engulfment adaptor phosphotyrosine‐binding domain‐containing 1 (GULP1) regulates intracellular trafficking of glycosphingolipids and cholesterol, suggesting its close association with lipid metabolism. However, the role of GULP1 in adipocytes remains unknown. Therefore, this study aimed to investigate the function of GULP1 in adipogenesis, glucose uptake, and the insulin signaling pathway in adipocytes. A 3T3‐L1 cell line with Gulp1 knockdown (shGulp1) and a 3T3‐L1 control group (U6) were established. Changes in shGulp1 cells due to GULP1 deficiency were examined and compared to those in U6 cells using microarray analysis. Glucose uptake was monitored via insulin stimulation in shGulp1 and U6 cells using a 2‐NBDG glucose uptake assay, and the insulin signaling pathway was investigated by western blot analysis. Adipogenesis was significantly delayed, lipid metabolism was altered, and several adipogenesis‐related genes were downregulated in shGulp1 cells compared to those in U6 cells. Microarray analysis revealed significant inhibition of peroxisome proliferator‐activated receptor signaling in shGulp1 cells compared with U6 cells. The production and secretion of adiponectin as well as the expression of adiponectin receptor were decreased in shGulp1 cells. In particular, compared with U6 cells, glucose uptake via insulin stimulation was significantly decreased in shGulp1 cells through the disturbance of ERK1/2 phosphorylation. This is the first study to identify the role of GULP1 in adipogenesis and insulin‐stimulated glucose uptake by adipocytes, thereby providing new insights into the differentiation and functions of adipocytes and the metabolism of lipids and glucose, which can help better understand metabolic diseases. [ABSTRACT FROM AUTHOR]