430 results on '"Scd1"'
Search Results
2. REV-ERBα inhibitor rescues MPTP/MPP+-induced ferroptosis of dopaminergic neuron through regulating FASN/SCD1 signaling pathway
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Wang, Xiaoyu, Wang, Mingmei, Zhi, Hui, Li, Jingwei, and Guo, Dongkai
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- 2024
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3. Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders
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Xia, Yangliu, Zhang, Yang, Zhang, Zhipeng, Yan, Nana, Sawaswong, Vorthon, Sun, Lulu, Guo, Wanwan, Wang, Ping, Krausz, Kristopher W., Gavrilova, Oksana, Ntambi, James M., Hao, Haiping, Yan, Tingting, and Gonzalez, Frank J. more...
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- 2024
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4. Brain‐Derived Exosomal miR‐9‐5p Induces Ferroptosis in Traumatic Brain Injury‐Induced Acute Lung Injury by Targeting Scd1.
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Zhang, Yi, Sun, Chang, Wang, Bailun, Gu, Angran, Zhou, Ziyi, and Gu, Changping
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EXOSOMES , *LUNG injuries , *PROTEIN expression , *LABORATORY mice , *ANIMAL disease models - Abstract
Aims: This study aimed to explore the role and underlying mechanisms of brain‐derived exosomes in traumatic brain injury‐induced acute lung injury (TBI‐induced ALI), with a particular focus on the potential regulation of ferroptosis through miRNAs and Scd1. Methods: To elucidate TBI‐induced ALI, we used a TBI mouse model. Exosomes were isolated from the brains of these mice and characterized using TEM and NTA. LC–MS analysis revealed an increase in the level of ferroptosis in the lung tissues of mice with TBI. Subsequent miRNA and mRNA sequencing revealed the upregulation of miR‐9‐5p and the downregulation of Scd1 in the pulmonary tissues of these mice. Ferroptosis was assessed by quantifying the levels of ROS, MDA, and Fe2+ and the expression of proteins associated with ferroptosis. Results: TBI led to the release of exosomes enriched with miR‐9‐5p, which targeted Scd1 in lung tissue, thereby promoting ferroptosis. Treatment with antagomir 9‐5p reduced the level of ALI in TBI mice, indicating that exosomal miR‐9‐5p plays a significant role in TBI‐induced ALI. Conclusion: This study revealed that brain‐derived exosomal miR‐9‐5p mediates ferroptosis in TBI‐induced ALI by targeting Scd1. These findings may provide new insights into the complex interplay between TBI and ALI and highlight the potential of miR‐9‐5p as a target for the development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR] more...
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- 2024
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5. A guide to selecting high-performing antibodies for Stearoyl-CoA desaturase (SCD1) (UniProt ID: O00767) for use in western blot, immunoprecipitation, and immunofluorescence [version 1; peer review: awaiting peer review]
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Vera Ruíz Moleón, Charles Alende, Maryam Fotouhi, Sara González Bolívar, Riham Ayoubi, and Carl Laflamme
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Data Note ,Articles ,O00767 ,SCD ,SCD1 ,Steroyl-CoA desaturase ,antibody characterization ,antibody validation ,western blot ,immunoprecipitation ,immunofluorescence - Abstract
The enzyme stearoyl-CoA desaturase (SCD1) is a modulator of lipid metabolism by catalyzing the biosynthesis of mono-unsaturated fatty acids from saturated fatty acids. Understanding the specific mechanisms by which SCD1 plays in health and disease can provide novel insides in therapeutic targets, a process that would be facilitated by the availability of high-quality antibodies. Here we have characterized nine SCD1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs. more...
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- 2025
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6. Knock-Out of IKKepsilon Ameliorates Atherosclerosis and Fatty Liver Disease by Alterations of Lipid Metabolism in the PCSK9 Model in Mice.
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Weiss, Ulrike, Mungo, Eleonora, Haß, Michelle, Benning, Denis, Gurke, Robert, Hahnefeld, Lisa, Dorochow, Erika, Schlaudraff, Jessica, Schmid, Tobias, Kuntschar, Silvia, Meyer, Sofie, Medert, Rebekka, Freichel, Marc, Geisslinger, Gerd, and Niederberger, Ellen more...
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FATTY liver , *KNOCKOUT mice , *MONOUNSATURATED fatty acids , *ATHEROSCLEROTIC plaque , *LIPID metabolism - Abstract
The inhibitor-kappaB kinase epsilon (IKKε) represents a non-canonical IκB kinase that modulates NF-κB activity and interferon I responses. Inhibition of this pathway has been linked with atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD), yet the results are contradictory. In this study, we employed a combined model of hepatic PCSK9D377Y overexpression and a high-fat diet for 16 weeks to induce atherosclerosis and liver steatosis. The development of atherosclerotic plaques, serum lipid concentrations, and lipid metabolism in the liver and adipose tissue were compared between wild-type and IKKε knock-out mice. The formation and progression of plaques were markedly reduced in IKKε knockout mice, accompanied by reduced serum cholesterol levels, fat deposition, and macrophage infiltration within the plaque. Additionally, the development of a fatty liver was diminished in these mice, which may be attributed to decreased levels of multiple lipid species, particularly monounsaturated fatty acids, triglycerides, and ceramides in the serum. The modulation of several proteins within the liver and adipose tissue suggests that de novo lipogenesis and the inflammatory response are suppressed as a consequence of IKKε inhibition. In conclusion, our data suggest that the knockout of IKKε is involved in mechanisms of both atherosclerosis and MASLD. Inhibition of this pathway may therefore represent a novel approach to the treatment of cardiovascular and metabolic diseases. [ABSTRACT FROM AUTHOR] more...
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- 2024
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7. Molecular Cloning of the scd1 Gene and Its Expression in Response to Feeding Artificial Diets to Mandarin Fish (Siniperca chuatsi).
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Wang, Jiangjiang, Zhang, Lihan, Gao, Xiaowei, Sun, Yanfeng, Zhao, Chunlong, Gao, Xiaotian, and Wu, Chengbin
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MOLECULAR cloning , *GENE expression , *FORAGE fishes , *PEPTIDES , *GENETIC transcription , *FISH feeds - Abstract
Background/Objectives: Stearoyl-coenzyme A desaturase 1 (SCD1) plays a crucial role in fatty acid metabolism. However, its roles in the feeding habit transformation of mandarin fish (Siniperca chuatsi) remain largely unknown. Methods: Juvenile mandarin fish (10.37 ± 0.54)g were trained to feed on an artificial diet and then divided into artificial diet feeders and nonfeeders according to their feed preference. Afterwards, the scd1 gene of mandarin fish (Sc-scd1) was identified and characterized, and its transcription difference was determined between S. chuatsi fed live artificial diets and those fed prey fish. Results: Our results show that Sc-scd1 coding sequence is 1002 bp long, encoding 333 amino acids. The assumed Sc-SCD1 protein lacks a signal peptide, and it contains 1 N-linked glycosylation site, 24 phosphorylation sites, 4 transmembrane structures, and 3 conserved histidine elements. We found that Sc-SCD1 exhibits a high similarity with its counterparts in other fish by multiple alignments and phylogenetic analysis. The expression level of Sc-scd1 was detected with different expression levels in all tested tissues between male and female individuals fed either live prey fish or artificial diets. Conclusions: In particular, the Sc-scd1 expression level was the highest in the liver of both male and female mandarin fish fed artificial diets, indicating that scd1 genes may be associated with feed adaption of mandarin fish. Taken together, our findings offer novel perspectives on the potential roles of scd1 in specific domestication, and they provide valuable genetic information on feeding habits for the domestication of mandarin fish. [ABSTRACT FROM AUTHOR] more...
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- 2024
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8. Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models
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Nerea Moreno, Maria Sabater-Arcis, Teresa Sevilla, Manuel Perez Alonso, Jessica Ohana, Ariadna Bargiela, and Ruben Artero
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Oleic acid ,Fatty acid ,SCD1 ,Myoblast differentiation ,miR-7 ,MSI2 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed. Results We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts. Conclusions For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype. more...
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- 2024
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9. Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells
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Juwon Lee, Suin Jang, Jihye Im, Youngjin Han, Soochi Kim, HyunA Jo, Wenyu Wang, Untack Cho, Se Ik Kim, Aeran Seol, Boyun Kim, and Yong Sang Song
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Ovarian cancer ,Lipid metabolism ,SCD1 ,ER stress ,Apoptosis ,Gynecology and obstetrics ,RG1-991 - Abstract
Abstract Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis. more...
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- 2024
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10. Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models.
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Moreno, Nerea, Sabater-Arcis, Maria, Sevilla, Teresa, Alonso, Manuel Perez, Ohana, Jessica, Bargiela, Ariadna, and Artero, Ruben
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MYOTONIA atrophica ,MUSCLE cells ,DYSTROPHY ,MUSCULAR atrophy ,NEUROMUSCULAR diseases ,FATTY acids ,OLEIC acid ,SUGAMMADEX - Abstract
Background: We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed. Results: We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts. Conclusions: For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
- View/download PDF
11. Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells.
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Lee, Juwon, Jang, Suin, Im, Jihye, Han, Youngjin, Kim, Soochi, Jo, HyunA, Wang, Wenyu, Cho, Untack, Kim, Se Ik, Seol, Aeran, Kim, Boyun, and Song, Yong Sang
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CANCER cells ,OVARIAN cancer ,OVARIAN epithelial cancer ,CANCER cell growth ,UNFOLDED protein response ,CAUSE of death statistics - Abstract
Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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12. RASSF1A independence and early galectin‐1 upregulation in PIK3CA‐induced hepatocarcinogenesis: new therapeutic venues
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Scheiter, Alexander, Evert, Katja, Reibenspies, Lucas, Cigliano, Antonio, Annweiler, Katharina, Müller, Karolina, Pöhmerer, Laura‐Maria‐Giovanna, Xu, Hongwei, Cui, Guofei, Itzel, Timo, Materna‐Reichelt, Silvia, Coluccio, Andrea, Honarnejad, Kamran, Teufel, Andreas, Brochhausen, Christoph, Dombrowski, Frank, Chen, Xin, Evert, Matthias, Calvisi, Diego F, and Utpatel, Kirsten more...
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Digestive Diseases ,Rare Diseases ,Liver Disease ,Cancer ,Liver Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Carcinogenesis ,Carcinoma ,Hepatocellular ,Cell Line ,Tumor ,Class I Phosphatidylinositol 3-Kinases ,Galectin 1 ,Humans ,Liver Neoplasms ,Mice ,Mutation ,Phosphatidylinositol 3-Kinases ,Proto-Oncogene Proteins c-akt ,TOR Serine-Threonine Kinases ,Up-Regulation ,alpelisib ,galectin-1 ,hepatocellular carcinoma ,OTX008 ,SCD1 ,ZIP4 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Aberrant activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/mitogen-activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain-containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild-type mice by hydrodynamic tail vein injection combined with sleeping beauty-mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl-CoA desaturase-1 (SCD1). Galectin-1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co-inhibitory treatment with PIK3CA inhibitors and the galectin-1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues. more...
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- 2022
13. Genotype-Dependent Variations in Oxidative Stress Markers and Bioactive Proteins in Hereford Bulls: Associations with DGAT1, LEP, and SCD1 Genes
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Piotr Kostusiak, Emilia Bagnicka, Beata Żelazowska, Magdalena Zalewska, Tomasz Sakowski, Jan Slósarz, Marcin Gołębiewski, and Kamila Puppel
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genetic variations ,DGAT1 ,LEP ,SCD1 ,oxidative stress ,beef ,Microbiology ,QR1-502 - Abstract
The objective of this study is to assess the influence of genetic polymorphisms in DGAT1, LEP, and SCD1 on the oxidative stress biomarkers and bioactive protein levels in Hereford bulls. A total of sixty-eight bulls were analyzed at 22 months of age to assess growth metrics and carcass quality, with a focus on polymorphisms in these genes. The key markers of oxidative stress, including malondialdehyde (MDA), and the activities of antioxidant enzymes such as glutathione reductase (GluRed), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were measured, alongside bioactive compounds like taurine, carnosine, and anserine. The results show that the TT genotype of DGAT1 is linked to significantly higher MDA levels, reflecting increased lipid peroxidation, but is also associated with higher GluRed and GPx activities and elevated levels of taurine, carnosine, and anserine, suggesting an adaptive response to oxidative stress. The LEP gene analysis revealed that the CC genotype had the highest MDA levels but also exhibited increased GPx and SOD activities, with the CT genotype showing the highest SOD activity and the TT genotype the highest total antioxidant status (TAS). The SCD1 AA genotype displayed the highest activities of GluRed, GPx, and SOD, indicating a more effective antioxidant defence, while the VA genotype had the highest MDA levels and the VV genotype showed lower MDA levels, suggesting protective effects against oxidative damage. These findings highlight genotype specific variations in the oxidative stress markers and bioactive compound levels, providing insights into the genetic regulation of oxidative stress and antioxidant defences, which could inform breeding strategies for improving oxidative stress resistance in livestock and managing related conditions. more...
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- 2024
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14. Overexpression of ZNF488 supports pancreatic cancer cell proliferation and tumorigenesis through inhibition of ferroptosis via regulating SCD1-mediated unsaturated fatty acid metabolism
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Qifeng Xiao, Zhongmin Lan, Shuisheng Zhang, Hu Ren, Shunda Wang, Peng Wang, Lin Feng, Dan Li, Chengfeng Wang, Xiaofeng Bai, and Jianwei Zhang
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Pancreatic cancer ,ZNF488 ,Ferroptosis ,SCD1 ,Gemcitabine ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Pancreatic cancer is a malignancy with high mortality. Once diagnosed, effective treatment strategies are limited and the five-year survival is extremely poor. Recent studies have shown that zinc finger proteins play important roles in tumorigenesis, including pancreatic cancer. However, it remains unknown on the clinical significance, function and underlying mechanisms of zinc finger protein 488 (ZNF488) during the development of pancreatic cancer. Methods The clinical relevance of ZNF488 and stearoyl-CoA desaturase 1 (SCD1) was examined by analyzing the data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of the tissue microarray. Gain-of-function and loss-of-function experiments were performed by transfecting the cells with overexpressing lentivirus and siRNAs or shRNA lentivirus, respectively. The function of ZNF488 in pancreatic cancer was assessed by CCK8, colony formation, EdU staining, PI/Annexin V staining and xenografted tumorigenesis. Chip-qPCR assay was conducted to examine the interaction between ZNF488 and the promoter sequence of SCD1. Transcription activity was measured by dual luciferase reporter assay. mRNA and protein expression was detected by qRT-PCR and immunoblotting experiment, respectively. Fatty acid was quantified by gas chromatography mass spectrometry. Results ZNF488 was overexpressed in pancreatic cancer samples compared with normal tissues. High expression of ZNF488 predicted the poor prognosis of the patients. In vitro, ZNF488 upregulation contributed to the EuU cooperation, proliferation and colony formation of MIAPaCa-2 and PANC-1 cells. Based on PI/Annexin V and trypan blue staining results, we showed that ZNF488 suppressed the ferroptosis and apoptosis of pancreatic cancer cells. Mechanistically, ZNF488 directly interacted with the promoter sequence of SCD1 gene and promoted its transcription activity, which resulted in enhanced palmitoleic and oleic acid production, as well as the peroxidation of fatty acid. In vivo, ZNF488 overexpression promoted the xenograted tumorigenesis of PANC-1, which was reversed by SCD1 knockdown. Importantly, combination of erastin and SCD1 inhibitors A939572 completely blunted the growth of ZNF488 overexpressed MIAPaCa-2 and PANC-1 cells. Usage of A939572 or erastin recovered the sensitivity of pancreatic cancer cells to the treatment of gemcitabine. Lastly, we found a positive correlation between ZNF488 and SCD1 in pancreatic cancer patients based on TCGA and immunohistochemical staining results. Conclusion Overexpression of ZNF488 suppresses the ferroptosis and apoptosis to support the growth and tumorigenesis of pancreatic cancer through augmentation of SCD1-mediated unsaturated fatty acid metabolism. Combination of SCD1 inhibitors, ferroptosis inducers or gemcitabine could be applied for the treatment of pancreatic cancer with overexpression of ZNF488. more...
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- 2023
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15. Scd1 and monounsaturated lipids are required for autophagy and survival of adipocytes
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Hiroyuki Mori, Sydney K. Peterson, Rachel C. Simmermon, Katherine A. Overmyer, Akira Nishii, Emma Paulsson, Ziru Li, Annie Jen, Romina M. Uranga, Jessica N. Maung, Warren T. Yacawych, Kenneth T. Lewis, Rebecca L. Schill, Taryn Hetrick, Ryo Seino, Ken Inoki, Joshua J. Coon, and Ormond A. MacDougald more...
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Scd1 ,Stearoyl CoA Desaturase 1 ,ADCD ,Autophagy-dependent cell death ,BMAT ,Bone marrow adipose tissue ,Internal medicine ,RC31-1245 - Abstract
Objective: Exposure of adipocytes to ‘cool’ temperatures often found in the periphery of the body induces expression of Stearoyl-CoA Desaturase-1 (Scd1), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. The goal of this study is to further investigate the roles of Scd in adipocytes. Method: In this study, we employed Scd1 knockout cells and mouse models, along with pharmacological Scd1 inhibition to dissect the enzyme's function in adipocyte physiology. Results: Our study reveals that production of monounsaturated lipids by Scd1 is necessary for fusion of autophagosomes to lysosomes and that with a Scd1-deficiency, autophagosomes accumulate. In addition, Scd1-deficiency impairs lysosomal and autolysosomal acidification resulting in vacuole accumulation and eventual cell death. Blocking autophagosome formation or supplementation with monounsaturated fatty acids maintains vitality of Scd1-deficient adipocytes. Conclusion: This study demonstrates the indispensable role of Scd1 in adipocyte survival, with its inhibition in vivo triggering autophagy-dependent cell death and its depletion in vivo leading to the loss of bone marrow adipocytes. more...
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- 2024
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16. Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice
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Lucia Cilenti, Jacopo Di Gregorio, Rohit Mahar, Fei Liu, Camilla T. Ambivero, Muthu Periasamy, Matthew E. Merritt, and Antonis S. Zervos
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MUL1 ,SCD1 ,lipogenesis ,obesity ,mitophagy ,Biology (General) ,QH301-705.5 - Abstract
Obesity is a growing epidemic affecting millions of people worldwide and a major risk factor for a multitude of chronic diseases and premature mortality. Accumulating evidence suggests that mitochondria have a profound role in diet-induced obesity and the associated metabolic changes, but the molecular mechanisms linking mitochondria to obesity remain poorly understood. Our studies have identified a new function for mitochondrial MUL1 E3 ubiquitin ligase, a protein known to regulate mitochondrial dynamics and mitophagy, in the control of energy metabolism and lipogenesis. Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype that is resistant to high-fat diet (HFD)-induced obesity and metabolic syndrome. Several metabolic and lipidomic pathways are perturbed in the liver and white adipose tissue (WAT) of Mul1(−/−) animals on HFD, including the one driven by Stearoyl-CoA Desaturase 1 (SCD1), a pivotal regulator of lipid metabolism and obesity. In addition, key enzymes crucial for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are also modulated in the absence of MUL1. The concerted action of these enzymes, in the absence of MUL1, results in diminished fat storage and heightened fatty acid oxidation. Our findings underscore the significance of MUL1-mediated mitophagy in regulating lipogenesis and adiposity, particularly in the context of HFD. Consequently, our data advocate the potential of MUL1 as a therapeutic target for drug development in the treatment of obesity, insulin resistance, NAFLD, and cardiometabolic diseases. more...
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- 2024
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17. Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer, from bench to bed.
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Guo, Zhengyang, Huo, Xiao, Li, Xianlong, Jiang, Changtao, and Xue, Lixiang
- Abstract
Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. The expression of SCD1 is increased in many cancers, and the altered expression contributes to the proliferation, invasion, sternness and chemoresistance of cancer cells. Recently, more evidence has been reported to further support the important role of SCD1 in cancer, and the regulation mechanism of SCD1 has also been focused. Multiple factors are involved in the regulation of SCD1, including metabolism, diet, tumor microenvironment, transcription factors, non-coding RNAs, and epigenetics modification. Moreover, SCD1 is found to be involved in regulating ferroptosis resistance. Based on these findings, SCD1 has been considered as a potential target for cancer treatment. However, the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity. This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
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18. A Scd1-mediated metabolic alteration participates in liver responses to low-dose bavachin
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Pan Shen, Zhi-Jie Bai, Lei Zhou, Ning-Ning Wang, Zhe-Xin Ni, De-Zhi Sun, Cong-Shu Huang, Yang-Yi Hu, Cheng-Rong Xiao, Wei Zhou, Bo-Li Zhang, and Yue Gao
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Bavachin ,Hepatotoxicity ,Scd1 ,Lipid metabolism ,Single-cell RNA-Seq ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Hepatotoxicity induced by bioactive constituents in traditional Chinese medicines or herbs, such as bavachin (BV) in Fructus Psoraleae, has a prolonged latency to overt drug-induced liver injury in the clinic. Several studies have described BV-induced liver damage and underlying toxicity mechanisms, but little attention has been paid to the deciphering of organisms or cellular responses to BV at no-observed-adverse-effect level, and the underlying molecular mechanisms and specific indicators are also lacking during the asymptomatic phase, making it much harder for early recognition of hepatotoxicity. Here, we treated mice with BV for 7 days and did not detect any abnormalities in biochemical tests, but found subtle steatosis in BV-treated hepatocytes. We then profiled the gene expression of hepatocytes and non-parenchymal cells at single-cell resolution and discovered three types of hepatocyte subsets in the BV-treated liver. Among these, the hepa3 subtype suffered from a vast alteration in lipid metabolism, which was characterized by enhanced expression of apolipoproteins, carboxylesterases, and stearoyl-CoA desaturase 1 (Scd1). In particular, increased Scd1 promoted monounsaturated fatty acids (MUFAs) synthesis and was considered to be related to BV-induced steatosis and polyunsaturated fatty acids (PUFAs) generation, which participates in the initiation of ferroptosis. Additionally, we demonstrated that multiple intrinsic transcription factors, including Srebf1 and Hnf4a, and extrinsic signals from niche cells may regulate the above-mentioned molecular events in BV-treated hepatocytes. Collectively, our study deciphered the features of hepatocytes in response to BV insult, decoded the underlying molecular mechanisms, and suggested that Scd1 could be a hub molecule for the prediction of hepatotoxicity at an early stage. more...
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- 2023
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19. BACE1 and SCD1 are associated with neurodegeneration.
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Bedoya-Guzmán, Ferley A., Pacheco-Herrero, Mar, Salomon-Cruz, Ivan Daniel, Barrera-Sandoval, Angela Maria, Gutierrez Vargas, Johanna Andrea, Villamil-Ortiz, Javier Gustavo, Lanau, Carlos Andres Villegas, David Arias-Londoño, Julián, Area-Gomez, Estela, and Cardona Gomez, Gloria Patricia more...
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LIPID analysis ,COGNITION disorders ,CADASIL syndrome ,ENDOTHELIAL cells ,IN vitro studies ,KRUSKAL-Wallis Test ,STATISTICS ,RESEARCH ,BIOLOGICAL models ,ALZHEIMER'S disease ,MONOUNSATURATED fatty acids ,HIPPOCAMPUS (Brain) ,IN vivo studies ,ANALYSIS of variance ,CONFIDENCE intervals ,ANIMAL experimentation ,MICROSCOPY ,INFLAMMATION ,WESTERN immunoblotting ,IMMUNOHISTOCHEMISTRY ,ONE-way analysis of variance ,MULTIVARIATE analysis ,PROTEIN precursors ,PRECIPITIN tests ,RATS ,T-test (Statistics) ,COMPARATIVE studies ,RESEARCH funding ,DEMENTIA ,MASS spectrometry ,FLUORESCENT antibody technique ,DESCRIPTIVE statistics ,FACTOR analysis ,OXIDOREDUCTASES ,PHOSPHOLIPIDS ,DATA analysis ,STATISTICAL correlation ,NEURODEGENERATION ,CEREBRAL ischemia - Abstract
Introduction: Proteolytic processing of amyloid protein precursor by b-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction. Methods: In this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach. Results: Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), representedmainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL. Conclusion: Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids. [ABSTRACT FROM AUTHOR] more...
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- 2023
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20. MiR-3180 inhibits hepatocellular carcinoma growth and metastasis by targeting lipid synthesis and uptake
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Jie Hong, Jie Liu, Yanan Zhang, Lihua Ding, and Qinong Ye
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Lipid synthesis ,Lipid transport ,miR-3180 ,SCD1 ,CD36 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Purpose Reprogrammed lipid metabolism is a hallmark of cancer that provides energy, materials, and signaling molecules for rapid cancer cell growth. Cancer cells acquire fatty acids primarily through de novo synthesis and uptake. Targeting altered lipid metabolic pathways is a promising anticancer strategy. However, their regulators have not been fully investigated, especially those targeting both synthesis and uptake. Methods Immunohistochemistry was performed on samples from patients with hepatocellular carcinoma (HCC) to establish the correlation between miR-3180, stearoyl-CoA desaturase-1 (SCD1), and CD36 expression, quantified via qRT-PCR and western blotting. The correlation was analyzed using a luciferase reporter assay. Cell proliferation, migration, and invasion were analyzed using CCK-8, wound healing, and transwell assays, respectively. Oil Red O staining and flow cytometry were used to detect lipids. Triglycerides and cholesterol levels were analyzed using a reagent test kit. CY3-labeled oleic acid transport was analyzed using an oleic acid transport assay. Tumor growth and metastasis were detected in vivo in a xenograft mouse model. Results MiR-3180 suppressed de novo fatty acid synthesis and uptake by targeting the key lipid synthesis enzyme SCD1 and key lipid transporter CD36. MiR-3180 suppressed HCC cell proliferation, migration, and invasion in an SCD1- and CD36-dependent manner in vitro. The mouse model demonstrated that miR-3180 inhibits HCC tumor growth and metastasis by inhibiting SCD1- and CD36-mediated de novo fatty acid synthesis and uptake. MiR-3180 expression was downregulated in HCC tissues and negatively correlated with SCD1 and CD36 levels. Patients with high miR-3180 levels showed better prognosis than those with low levels. Conclusions Our investigation indicates that miR-3180 is a critical regulator involved in de novo fatty acid synthesis and uptake, which inhibits HCC tumor growth and metastasis by suppressing SCD1 and CD36. Therefore, miR-3180 is a novel therapeutic target and prognostic indicator for patients with HCC. more...
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- 2023
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21. TGF-β1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts
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Zili Zhou, Shixiu Liang, Zicong Zhou, Jieyi Liu, Jinming Zhang, Xiaojing Meng, Fei Zou, Haijin Zhao, Changhui Yu, and Shaoxi Cai
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House dust mite ,Airway remodeling ,Fibroblasts ,SCD1 ,SREBP1 ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Lung fibroblast activation is associated with airway remodeling during asthma progression. Stearoyl-CoA desaturase 1 (SCD1) plays an important role in the response of fibroblasts to growth factors. This study aimed to explore the effects of SCD1 on fibroblast activation induced by transforming growth factor-β1 (TGF-β1) and the role of the phosphatidylinositol-3-kinase-AKT serine-threonine protein kinase-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway on the regulation of SCD1 expression in airway remodeling. Methods Female C57BL/6 mice were sensitized and challenged with house dust mites to generate a chronic asthma model. The inhibitor of SCD1 was injected i.g. before each challenge. The airway hyper-responsiveness to methacholine was evaluated, and airway remodeling and airway inflammation were assessed by histology. The effects of SCD1 on fibroblast activation were evaluated in vitro using an SCD1 inhibitor and oleic acid and via the knockdown of SCD1. The involvement of the PI3K-Akt-mTOR-sterol regulatory element-binding protein 1 (SREBP1) pathway in lung fibroblasts was investigated using relevant inhibitors. Results The expression of SCD1 was increased in fibroblasts exposed to TGF-β1. The inhibition of SCD1 markedly ameliorated airway remodeling and lung fibroblast activation in peripheral airways. The knockdown or inhibition of SCD1 resulted in significantly reduced extracellular matrix production in TGF-β1-treated fibroblasts, but this effect was reversed by the addition of exogenous oleic acid. The PI3K-Akt-mTOR-SREBP1 pathway was found to be involved in the regulation of SCD1 expression and lung fibroblast activation. Conclusions The data obtained in this study indicate that SCD1 expression contributes to fibroblast activation and airway remodeling and that the inhibition of SCD1 may be a therapeutic strategy for airway remodeling in asthma. more...
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- 2023
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22. PTHrP Regulates Fatty Acid Metabolism via Novel lncRNA in Breast Cancer Initiation and Progression Models.
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Zhang, Rui, Li, Jiarong, Badescu, Dunarel, Karaplis, Andrew C., Ragoussis, Jiannis, and Kremer, Richard
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RNA analysis , *DISEASE progression , *HYPERCALCEMIA , *SEQUENCE analysis , *CANCER invasiveness , *ANIMAL experimentation , *SIGNAL peptides , *NEOPLASTIC cell transformation , *PARATHYROID hormone , *CELLULAR signal transduction , *CELL cycle , *CELL survival , *GENE expression , *RESEARCH funding , *TRANSGENIC animals , *OXIDOREDUCTASES , *CELL lines , *POLYMERASE chain reaction , *BREAST tumors , *FATTY acids , *MICE , *METABOLISM - Abstract
Simple Summary: The 5-year survival rate for women with metastatic breast cancer is 29%. Potential biomarker identification is important for new treatment modalities in affected patients. Previous studies have shown that Parathyroid hormone-related peptide (PTHrP) plays a critical role in breast cancer growth and metastasis. Our study aimed to use a genetically modified breast cancer mouse model to precisely examine the role of PTHrP from early primary breast cancer initiation to late progression. We identified a novel long non-coding RNA (lncRNA), a new target for fatty acid metabolism that can be regulated via PTHrP in our unique mouse breast cancer model. We confirmed that a potential human lncRNA, OLMALINC, plays a similar role in fatty acid metabolism that can be regulated via PTHrP and validated our mouse findings in human breast cancer cell lines. Genetically engineered mouse models provide valuable tools to study the molecular metabolism for breast cancer progression. Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling mechanisms using lineage tracing have not yet been carefully analyzed. Here, we generated Pthrpflox/flox; Cre+ mT/mG mice (KO) and Pthrpwt/wt; Cre+ mT/mG tumor mice (WT) to examine the signaling pathways under the control of PTHrP from the early to late stages of tumorigenesis. GFP+ mammary epithelial cells were further enriched for subsequent RNA sequencing (RNAseq) analyses. We observed significant upregulation of cell cycle signaling and fatty acid metabolism in PTHrP WT tumors, which are linked to tumor initiation and progression. Next, we observed that the expression levels of a novel lncRNA, GM50337, along with stearoyl-Coenzyme A desaturase 1 (Scd1) are significantly upregulated in PTHrP WT but not in KO tumors. We further validated a potential human orthologue lncRNA, OLMALINC, together with SCD1 that can be regulated via PTHrP in human BC cell lines. In conclusion, these novel findings could be used to develop targeted strategies for the treatment of BC and its metastatic complications. [ABSTRACT FROM AUTHOR] more...
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- 2023
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23. A Scd1-mediated metabolic alteration participates in liver responses to low-dose bavachin.
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Shen, Pan, Bai, Zhi-Jie, Zhou, Lei, Wang, Ning-Ning, Ni, Zhe-Xin, Sun, De-Zhi, Huang, Cong-Shu, Hu, Yang-Yi, Xiao, Cheng-Rong, Zhou, Wei, Zhang, Bo-Li, and Gao, Yue
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MONOUNSATURATED fatty acids ,UNSATURATED fatty acids ,LIVER ,GENE expression profiling ,CHINESE medicine ,TRANSCRIPTION factors - Abstract
Hepatotoxicity induced by bioactive constituents in traditional Chinese medicines or herbs, such as bavachin (BV) in Fructus Psoraleae, has a prolonged latency to overt drug-induced liver injury in the clinic. Several studies have described BV-induced liver damage and underlying toxicity mechanisms, but little attention has been paid to the deciphering of organisms or cellular responses to BV at no-observed-adverse-effect level, and the underlying molecular mechanisms and specific indicators are also lacking during the asymptomatic phase, making it much harder for early recognition of hepatotoxicity. Here, we treated mice with BV for 7 days and did not detect any abnormalities in biochemical tests, but found subtle steatosis in BV-treated hepatocytes. We then profiled the gene expression of hepatocytes and non-parenchymal cells at single-cell resolution and discovered three types of hepatocyte subsets in the BV-treated liver. Among these, the hepa3 subtype suffered from a vast alteration in lipid metabolism, which was characterized by enhanced expression of apolipoproteins, carboxylesterases, and stearoyl-CoA desaturase 1 (Scd1). In particular, increased Scd1 promoted monounsaturated fatty acids (MUFAs) synthesis and was considered to be related to BV-induced steatosis and polyunsaturated fatty acids (PUFAs) generation, which participates in the initiation of ferroptosis. Additionally, we demonstrated that multiple intrinsic transcription factors, including Srebf1 and Hnf4a , and extrinsic signals from niche cells may regulate the above-mentioned molecular events in BV-treated hepatocytes. Collectively, our study deciphered the features of hepatocytes in response to BV insult, decoded the underlying molecular mechanisms, and suggested that Scd1 could be a hub molecule for the prediction of hepatotoxicity at an early stage. [Display omitted] • Transcriptome atlas is deciphered in BV-treated hepatocytes at asymptomatic stage. • Lipid homeostasis imbalance is the core of cellular responses to low-dose BV. • Scd1 is a potential indicator for the early prediction of BV-induced hepatotoxicity. [ABSTRACT FROM AUTHOR] more...
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- 2023
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24. α-Tocopherol-13′-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation.
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Liao, Sijia, Gollowitzer, André, Börmel, Lisa, Maier, Charlotte, Gottschalk, Luisa, Werz, Oliver, Wallert, Maria, Koeberle, Andreas, and Lorkowski, Stefan
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CELL cycle , *STEROL regulatory element-binding proteins , *CELL death , *MONOUNSATURATED fatty acids , *SATURATED fatty acids , *LIPIDS , *MEMBRANE lipids - Abstract
α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G0/G1 cell cycle arrest and apoptosis in macrophages triggered by α-T-13′-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13′-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13′-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13′-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1). [ABSTRACT FROM AUTHOR] more...
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- 2023
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25. BACE1 and SCD1 are associated with neurodegeneration
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Ferley A. Bedoya-Guzmán, Mar Pacheco-Herrero, Ivan Daniel Salomon-Cruz, Angela Maria Barrera-Sandoval, Johanna Andrea Gutierrez Vargas, Javier Gustavo Villamil-Ortiz, Carlos Andres Villegas Lanau, Julián David Arias-Londoño, Estela Area-Gomez, and Gloria Patricia Cardona Gomez more...
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BACE1 ,SCD1 ,neurodegeneration ,phospholipids ,PUFAs ,pro-inflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionProteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction.MethodsIn this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach.ResultsOur findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL.ConclusionTherefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids. more...
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- 2023
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26. Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications
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Kwon, Doyoung, Kim, Sung-Mi, and Correia, Maria Almira
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Digestive Diseases ,Liver Disease ,Chronic Liver Disease and Cirrhosis ,Hepatitis ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Cytochromes P450 ,Endoplasmic reticulum- associated degradation ,CHIP E3 ubiquitin ligase ,gp78/AMFR E3 ubiquitin ligase ,JNK1 ,AMPKI ,Non-alcoholic fatty liver disease ,Non-alcoholic steatohepatitis ,3MA ,3-methyladenine ,AAA ,ATPases associated with various cellular activities ,ACC1 ,acetyl-CoA carboxylase 1 ,ACC2 ,acetyl-CoA carboxylase 2 ,ACHE ,acetylcholinesterase ,ACOX1 ,acyl-CoA oxidase 1 ,ALD ,autophagic-lysosomal degradation ,AMPK1 ,AP-1 ,activator protein 1 ,ASK1 ,apoptosis signal-regulating kinase ,ATF2 ,activating transcription factor 2 ,AdipoR1 ,gene of adiponectin receptor 1 ,Atg14 ,autophagy-related 14 ,CBZ ,carbamazepine ,CHIP ,carboxy-terminus of Hsc70-interacting protein ,Endoplasmic reticulum-associated degradation ,FOXO ,forkhead box O ,Fas ,fatty acid synthase ,GAPDH ,glyceraldehyde 3-phosphate dehydrogenase ,INH ,isoniazid ,IRS1 ,insulin receptor substrate 1 ,Il-1β ,interleukin 1 β ,Il-6 ,interleukin 6 ,Insig1 ,insulin-induced gene 1 ,Lpl ,lipoprotein lipase ,Mcp1 ,chemokine (C–C motif) ligand 1 ,Pgc1 ,peroxisome proliferator-activated receptor coactivator 1 ,SREBP1c ,sterol regulatory element binding transcription factor 1c ,Scd1 ,stearoyl-coenzyme A desaturase ,Tnf ,tumor necrosis factor ,UPD ,ubiquitin (Ub)-dependent proteasomal degradation ,Ub ,ubiquitin ,gp78/AMFR ,autocrine motility factor receptor ,shRNAi ,shRNA interference ,Pharmacology and pharmaceutical sciences - Abstract
The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions. more...
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- 2020
27. MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors
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Ye Zeng, Chen Haidi, Ji Shunrong, Hu Yuheng, Lou Xin, Zhang Wuhu, Jing Desheng, Fan Guixiong, Zhang Yue, Chen Xuemin, Zhuo Qifeng, Chen Jie, Xu Xiaowu, Yu Xianjun, Xu Jin, Qin Yi, and Gao Heli
- Subjects
pancreatic neuroendocrine tumor ,MEN1 ,ferroptosis ,mTOR signaling ,SCD1 ,Biochemistry ,QD415-436 ,Genetics ,QH426-470 - Abstract
Pancreatic neuroendocrine tumor (pNET) is the second most common malignant tumors of the pancreas. Multiple endocrine neoplasia 1 ( MEN1) is the most frequently mutated gene in pNETs and MEN1-encoded protein, menin, is a scaffold protein that interacts with transcription factors and chromatin-modifying proteins to regulate various signaling pathways. However, the role of MEN1 in lipid metabolism has not been studied in pNETs. In this study, we perform targeted metabolomics analysis and find that MEN1 promotes the generation and oxidation of polyunsaturated fat acids (PUFAs). Meanwhile lipid peroxidation is a hallmark of ferroptosis, and we confirm that MEN1 promotes ferroptosis by inhibiting the activation of mTOR signaling which is the central hub of metabolism. We show that stearoyl-coA desaturase (SCD1) is the downstream of MEN1-mTOR signaling and oleic acid (OA), a metabolite of SCD1, recues the lipid peroxidation caused by MEN1 overexpression. The negative correlation between MEN1 and SCD1 is further verified in clinical specimens. Furthermore, we find that BON-1 and QGP-1 cells with MEN1 overexpression are more sensitive to everolimus, a widely used drug in pNETs that targets mTOR signaling. In addition, combined use everolimus with ferroptosis inducer, RSL3, possesses a more powerful ability to kill cells, which may provide a new strategy for the comprehensive therapy of pNETs. more...
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- 2022
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28. A novel insight into the key gene signature associated with the immune landscape in the progression of sarcopenia
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Zi-Le Shen, Wen-Hao Chen, Zhang Liu, Ding-Ye Yu, Wei-Zhe Chen, Wang-Fu Zang, Peng Zhang, Xia-Lin Yan, and Zhen Yu
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Sarcopenia ,Immune microenvironment ,Myosteatosis ,SCD1 ,Lipid metabolism ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Sarcopenia is an age-related skeletal muscle disorder that causes falls, disability and death in the elderly, but its exact mechanism remains unknown. In this study, we merged three GEO datasets into the expression profiles of 118 samples and screened 22 differentially expressed genes (DEGs) as candidate genes. Pathway analysis demonstrated that the functional enrichment of DEGs is mainly in the cellular response to insulin stimulus, PPAR signaling pathway and other metabolism-related pathways. Then, we identified six key genes by machine learning, which were confirmed to be closely associated with sarcopenia by bioinformatics analysis. It was experimentally verified that SCD1 exhibits the most substantial alterations in the progression of sarcopenia with disturbed lipid metabolism and myosteatosis. In addition, the immune microenvironment of sarcopenia was found to be affected by these key genes, with Th17 cells down-regulated and NK cells up-regulated. Sarcopenic patients consequently presented a more significant systemic inflammatory state with higher CAR (p = 0.028) and PAR (p = 0.018). For the first time, we identified key genes in sarcopenia with high-throughput data and demonstrated that key genes can regulate the progression of sarcopenia by affecting the immune microenvironment. Among them, SCD1 may influence lipid metabolism and myosteatosis process. Screening of key genes and analyzing of immune microenvironment provide a more accurate target for treating sarcopenia. more...
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- 2023
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29. Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 (Adgrf1)
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Mengyao Wu, Tak-Ho Lo, Liping Li, Jia Sun, Chujun Deng, Ka-Ying Chan, Xiang Li, Steve Ting-Yuan Yeh, Jimmy Tsz Hang Lee, Pauline Po Yee Lui, Aimin Xu, and Chi-Ming Wong
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obesity ,fatty liver ,lipid metabolism ,gpr110 ,SCD1 ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Background: Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism. Methods: We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver. Results: The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively. Conclusions: These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting Adgrf1. Funding: This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ. more...
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- 2023
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30. Stearoyl-CoA Desaturase 1 as a Therapeutic Biomarker: Focusing on Cancer Stem Cells.
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Min, Jin-Young and Kim, Do-Hee
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MONOUNSATURATED fatty acids , *SATURATED fatty acids , *CANCER stem cells , *BIOMARKERS , *LIPID metabolism , *GENE expression - Abstract
The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity. [ABSTRACT FROM AUTHOR] more...
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- 2023
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31. MiR-3180 inhibits hepatocellular carcinoma growth and metastasis by targeting lipid synthesis and uptake.
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Hong, Jie, Liu, Jie, Zhang, Yanan, Ding, Lihua, and Ye, Qinong
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LIPID synthesis ,HEPATOCELLULAR carcinoma ,CANCER cell growth ,STAINS & staining (Microscopy) ,OLEIC acid - Abstract
Purpose: Reprogrammed lipid metabolism is a hallmark of cancer that provides energy, materials, and signaling molecules for rapid cancer cell growth. Cancer cells acquire fatty acids primarily through de novo synthesis and uptake. Targeting altered lipid metabolic pathways is a promising anticancer strategy. However, their regulators have not been fully investigated, especially those targeting both synthesis and uptake. Methods: Immunohistochemistry was performed on samples from patients with hepatocellular carcinoma (HCC) to establish the correlation between miR-3180, stearoyl-CoA desaturase-1 (SCD1), and CD36 expression, quantified via qRT-PCR and western blotting. The correlation was analyzed using a luciferase reporter assay. Cell proliferation, migration, and invasion were analyzed using CCK-8, wound healing, and transwell assays, respectively. Oil Red O staining and flow cytometry were used to detect lipids. Triglycerides and cholesterol levels were analyzed using a reagent test kit. CY3-labeled oleic acid transport was analyzed using an oleic acid transport assay. Tumor growth and metastasis were detected in vivo in a xenograft mouse model. Results: MiR-3180 suppressed de novo fatty acid synthesis and uptake by targeting the key lipid synthesis enzyme SCD1 and key lipid transporter CD36. MiR-3180 suppressed HCC cell proliferation, migration, and invasion in an SCD1- and CD36-dependent manner in vitro. The mouse model demonstrated that miR-3180 inhibits HCC tumor growth and metastasis by inhibiting SCD1- and CD36-mediated de novo fatty acid synthesis and uptake. MiR-3180 expression was downregulated in HCC tissues and negatively correlated with SCD1 and CD36 levels. Patients with high miR-3180 levels showed better prognosis than those with low levels. Conclusions: Our investigation indicates that miR-3180 is a critical regulator involved in de novo fatty acid synthesis and uptake, which inhibits HCC tumor growth and metastasis by suppressing SCD1 and CD36. Therefore, miR-3180 is a novel therapeutic target and prognostic indicator for patients with HCC. [ABSTRACT FROM AUTHOR] more...
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- 2023
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32. Uncarboxylated Osteocalcin Decreases SCD1 by Activating AMPK to Alleviate Hepatocyte Lipid Accumulation.
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Wang, Danqing, Zhang, Miao, Xu, Jiaojiao, and Yang, Jianhong
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OSTEOCALCIN , *AMP-activated protein kinases , *NON-alcoholic fatty liver disease , *LIPIDS , *STAINS & staining (Microscopy) , *PROTEIN kinases - Abstract
Uncarboxylated osteocalcin (GluOC), a small-molecule protein specifically synthesized and secreted by osteoblasts, is important in the regulation of energy metabolism. In our previous study, GluOC was shown to be effective in ameliorating dyslipidemia and hepatic steatosis in KKAy mice. However, the underlying mechanism of GluOC action on hepatocytes has not been well validated. In this study, oleic acid/palmitic acid (OA/PA)-induced HepG2 and NCTC 1469 cells were used as non-alcoholic fatty liver disease (NAFLD) cell models, and triacylglycerol (TG) levels were measured by oil red O staining, Nile Red staining, and ELISA. The fatty acid synthesis-related protein expression was detected by real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. The results show that GluOC reduced triglyceride levels, and decreased the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and stearyl-coenzyme A desaturase 1 (SCD1). si-SCD1 mimicked the lipid accumulation-reducing effect of GluOC, while overexpression of SCD1 attenuated the effect of GluOC. In addition, GluOC activated AMP-activated protein kinase (AMPK) phosphorylation to affect lipid metabolism in hepatocytes. Overall, the results of this study suggest that GluOC decreases SCD1 by activating AMPK to alleviate hepatocyte lipid accumulation, which provides a new target for improving NAFLD in further research. [ABSTRACT FROM AUTHOR] more...
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- 2023
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33. RASSF1A independence and early galectin‐1 upregulation in PIK3CA‐induced hepatocarcinogenesis: new therapeutic venues
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Alexander Scheiter, Katja Evert, Lucas Reibenspies, Antonio Cigliano, Katharina Annweiler, Karolina Müller, Laura‐Maria‐Giovanna Pöhmerer, Hongwei Xu, Guofei Cui, Timo Itzel, Silvia Materna‐Reichelt, Andrea Coluccio, Kamran Honarnejad, Andreas Teufel, Christoph Brochhausen, Frank Dombrowski, Xin Chen, Matthias Evert, Diego F. Calvisi, and Kirsten Utpatel more...
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alpelisib ,galectin‐1 ,hepatocellular carcinoma ,OTX008 ,SCD1 ,ZIP4 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Aberrant activation of the phosphoinositide 3‐kinase (PI3K)/AKT/mTOR and Ras/mitogen‐activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain‐containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild‐type mice by hydrodynamic tail vein injection combined with sleeping beauty‐mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl‐CoA desaturase‐1 (SCD1). Galectin‐1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co‐inhibitory treatment with PIK3CA inhibitors and the galectin‐1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues. more...
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- 2022
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34. Icaritin Derivative IC2 Induces Cytoprotective Autophagy of Breast Cancer Cells via SCD1 Inhibition.
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Wang, Yi-Xuan, Jin, Yi-Yuan, Wang, Jie, Zhao, Zi-Cheng, Xue, Ke-Wen, Xiong, He, Che, Hui-Lian, Ge, Yun-Jun, and Wu, Guo-Sheng
- Subjects
- *
CANCER cells , *MITOGEN-activated protein kinases , *AUTOPHAGY , *BREAST cancer , *ADENOSINE monophosphate , *AMP-activated protein kinases - Abstract
Breast cancer is one of the most prevalent malignancies and the leading cause of cancer-associated mortality in China. Icaritin (ICT), a prenyl flavonoid derived from the Epimedium Genus, has been proven to inhibit the proliferation and stemness of breast cancer cells. Our previous study demonstrated that IC2, a derivative of ICT, could induce breast cancer cell apoptosis by Stearoyl-CoA desaturase 1 (SCD1) inhibition. The present study further investigated the mechanism of the inhibitory effects of IC2 on breast cancer cells in vitro and in vivo. Our results proved that IC2 could stimulate autophagy in breast cancer cells with the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling and mitogen-activated protein kinase (MAPK) signaling. Combination treatment of the AMPK inhibitor decreased IC2-induced autophagy while it markedly enhanced IC2-induced apoptosis. In common with IC2-induced apoptosis, SCD1 overexpression or the addition of exogenous oleic acid (OA) could also alleviate IC2-induced autophagy. In vivo assays additionally demonstrated that IC2 treatment markedly inhibited tumor growth in a mouse breast cancer xenograft model. Overall, our study was the first to demonstrate that IC2 induced cytoprotective autophagy by SCD1 inhibition in breast cancer cells and that the autophagy inhibitor markedly enhanced the anticancer activity of IC2. Therefore, IC2 was a potential candidate compound in combination therapy for breast cancer. [ABSTRACT FROM AUTHOR] more...
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- 2023
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35. Scd1 Deficiency in Early Embryos Affects Blastocyst ICM Formation through RPs-Mdm2-p53 Pathway.
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Niu, Huimin, Lei, Anmin, Tian, Huibin, Yao, Weiwei, Liu, Ying, Li, Cong, An, Xuetong, Chen, Xiaoying, Zhang, Zhifei, Wu, Jiao, Yang, Min, Huang, Jiangtao, Cheng, Fei, Zhao, Jianqing, Hua, Jinlian, Liu, Shimin, and Luo, Jun more...
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FATTY acid desaturase , *EMBRYOS , *EMBRYOLOGY , *MONOUNSATURATED fatty acids , *RIBOSOMES , *ORGANELLE formation , *BLASTOCYST - Abstract
Embryos contain a large number of lipid droplets, and lipid metabolism is gradually activated during embryonic development to provide energy. However, the regulatory mechanisms remain to be investigated. Stearoyl-CoA desaturase 1 (Scd1) is a fatty acid desaturase gene that is mainly involved in intracellular monounsaturated fatty acid production, which takes part in many physiological processes. Analysis of transcripts at key stages of embryo development revealed that Scd1 was important and expressed at an increased level during the cleavage and blastocyst stages. Knockout Scd1 gene by CRISPR/Cas9 from zygotes revealed a decrease in lipid droplets (LDs) and damage in the inner cell mass (ICM) formation of blastocyst. Comparative analysis of normal and knockout embryo transcripts showed a suppression of ribosome protein (RPs) genes, leading to the arrest of ribosome biogenesis at the 2-cell stage. Notably, the P53-related pathway was further activated at the blastocyst stage, which eventually caused embryonic development arrest and apoptosis. In summary, Scd1 helps in providing energy for embryonic development by regulating intra-embryonic lipid droplet formation. Moreover, deficiency activates the RPs-Mdm2-P53 pathway due to ribosomal stress and ultimately leads to embryonic development arrest. The present results suggested that Scd1 gene is essential to maintain healthy development of embryos by regulating energy support. [ABSTRACT FROM AUTHOR] more...
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- 2023
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36. TGF-β1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts.
- Author
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Zhou, Zili, Liang, Shixiu, Zhou, Zicong, Liu, Jieyi, Zhang, Jinming, Meng, Xiaojing, Zou, Fei, Zhao, Haijin, Yu, Changhui, and Cai, Shaoxi
- Subjects
TRANSFORMING growth factors ,METHACHOLINE chloride ,TOR proteins ,HOUSE dust mites ,CELLULAR signal transduction ,FIBROBLASTS ,EXTRACELLULAR matrix - Abstract
Background: Lung fibroblast activation is associated with airway remodeling during asthma progression. Stearoyl-CoA desaturase 1 (SCD1) plays an important role in the response of fibroblasts to growth factors. This study aimed to explore the effects of SCD1 on fibroblast activation induced by transforming growth factor-β1 (TGF-β1) and the role of the phosphatidylinositol-3-kinase-AKT serine-threonine protein kinase-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway on the regulation of SCD1 expression in airway remodeling. Methods: Female C57BL/6 mice were sensitized and challenged with house dust mites to generate a chronic asthma model. The inhibitor of SCD1 was injected i.g. before each challenge. The airway hyper-responsiveness to methacholine was evaluated, and airway remodeling and airway inflammation were assessed by histology. The effects of SCD1 on fibroblast activation were evaluated in vitro using an SCD1 inhibitor and oleic acid and via the knockdown of SCD1. The involvement of the PI3K-Akt-mTOR-sterol regulatory element-binding protein 1 (SREBP1) pathway in lung fibroblasts was investigated using relevant inhibitors. Results: The expression of SCD1 was increased in fibroblasts exposed to TGF-β1. The inhibition of SCD1 markedly ameliorated airway remodeling and lung fibroblast activation in peripheral airways. The knockdown or inhibition of SCD1 resulted in significantly reduced extracellular matrix production in TGF-β1-treated fibroblasts, but this effect was reversed by the addition of exogenous oleic acid. The PI3K-Akt-mTOR-SREBP1 pathway was found to be involved in the regulation of SCD1 expression and lung fibroblast activation. Conclusions: The data obtained in this study indicate that SCD1 expression contributes to fibroblast activation and airway remodeling and that the inhibition of SCD1 may be a therapeutic strategy for airway remodeling in asthma. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
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37. METTL3/miR-192-5p/SCD1 Axis Regulates Lipid Metabolism to Affect T Cell Differentiation in Asthma.
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Chen Z, Yan D, Guo S, Song Y, Zhang X, Gu W, Dong H, and Huang L
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- Animals, Humans, Mice, Male, Female, Mice, Inbred C57BL, Child, T-Lymphocytes metabolism, Asthma metabolism, MicroRNAs metabolism, MicroRNAs genetics, Lipid Metabolism, Cell Differentiation, Stearoyl-CoA Desaturase metabolism, Stearoyl-CoA Desaturase genetics, Methyltransferases metabolism, Methyltransferases genetics
- Abstract
Background: This study aimed to explore the mechanisms underlying T-cell differentiation in asthma. Methods and Results: Flow cytometry was performed to detect Th cells. LC-MS/MS was performed to assess lipid metabolism. HE staining was performed to assess the pathological changes of the lung tissues. ELISA was performed to detect cytokine levels. The results of quantitative real-time polymerase chain reaction (qRT-PCR) and western blot showed that miR-192-5p expression was decreased, while SCD1 expression was increased in CD4
+ T cells isolated from the peripheral blood of children with asthma. The dual luciferase reporter assay determined the direct interaction between miR-192-5p and SCD1. MiR-192-5p inhibitor reduced ASCL3 and PPARα, increased FASN and SREBP1c mRNA expression and protein levels in mouse spleen CD4+ T cells, and elevated Th2 and Th17 cells, but these effects were reversed by the SCD1 inhibitor. Oleic acid (OA) reduced Th1 cells and increased Th2 and Th17 cells in mouse spleen CD4+ T cells treated with an SCD1 inhibitor. Additionally, pri-miR-192-5p expression was increased in CD4+ T cells isolated from the peripheral blood of asthmatic children, and the deletion of METTL3 upregulated pri-miR-192-5p expression in an m6A-dependent manner. MiR-192-5p mimic and inhibitor both reversed miR-192-5p and SCD1 expression affected by overexpression or deletion of METTL3, both in vivo and in vitro . Furthermore, METTL3 overexpression attenuated lung inflammation, elevated Th1 cells, and reduced Th2 and Th17 cells in CD4+ T cells isolated from the peripheral blood of asthmatic mice. These effects were reversed by the miR-192-5p inhibitor. Conclusion: These results suggest that METTL3/miR-192-5p/SCD1 axis regulates lipid metabolism and affects T cell differentiation, thus affecting asthma progression. This study may provide novel insights into the pathogenesis of asthma and a new treatment strategy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Zhengrong Chen et al. Mediators of Inflammation published by John Wiley & Sons Ltd.) more...- Published
- 2025
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38. Combined Blockade of Lipid Uptake and Synthesis by CD36 Inhibitor and SCD1 siRNA Is Beneficial for the Treatment of Refractory Prostate Cancer.
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Chen J, Yu X, Yang G, Chen X, Gong C, Han L, Wang Y, Wang R, Wang L, and Yuan Y
- Abstract
Drug resistance is an important factor for prostate cancer (PCa) to progress into refractory PCa, and abnormal lipid metabolism usually occurs in refractory PCa, which presents great challenges for PCa therapy. Here, a cluster of differentiation 36 (CD36) inhibitor sulfosuccinimidyl oleate sodium (CD36i) and stearoyl-CoA desaturase 1 (SCD1) siRNA (siSCD1) are selected to inhibit lipid uptake and synthesis in PCa, respectively. To this end, a multiresponsive drug delivery nanosystem, HA@CD36i-TR@siSCD1 is designed. The hyaluronic acid (HA) gel "shell" of HA-TR nanosystem can release drugs in response to the acidic tumor microenvironment and hyaluronidase, and the tumor targeting (TR) cationic micellar "core" can release drugs in response to glutathione. This multiresponsive drug release is beneficial for the exogenous inhibition of lipid uptake by CD36i and the endogenous inhibition of lipid synthesis by siSCD1. The established HA-TR nanosystem has good tumor targeting ability and tumor penetration ability, and that HA@CD36i-TR@siSCD1 has good synergistic effects, which can significantly restrain the growth, invasion, and metastasis of PCa. Moreover, under high-fat conditions, the tumors are more sensitive to HA@CD36i-TR@siSCD1 treatment, almost no accumulation of lipid droplets is observed in HA@CD36i-TR@siSCD1-treated tumors, with enhanced antitumor immunity. Hence, this study provides a new treatment option for refractory PCa patients, especially those with a high-fat diet., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.) more...
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- 2024
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39. Inhibition of stearoyl-CoA desaturase 1 in the mouse impairs pancreatic islet morphogenesis and promotes loss of β-cell identity and α-cell expansion in the mature pancreas
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Aneta M. Dobosz, Justyna Janikiewicz, Ewelina Krogulec, Anna Dziewulska, Anna Ajduk, Marcin Szpila, Hanna Nieznańska, Andrzej A. Szczepankiewicz, Dorota Wypych, and Agnieszka Dobrzyn
- Subjects
SCD1 ,Pancreatic islets ,Alpha cells ,Beta cells ,DNA methylation ,Insulin ,Internal medicine ,RC31-1245 - Abstract
Abnormalities that characterize the pathophysiology of type 2 diabetes (T2D) include deficiencies of β-cells and the expansion of α-cells in pancreatic islets, manifested by lower insulin release and glucagon oversecretion. The molecular mechanisms that determine intra-islet interactions between pancreatic α- and β-cells are still not fully understood. The present study showed that stearoyl-coenzyme A (CoA) desaturase 1 (SCD1), an enzyme that is implicated in fatty acid metabolism, serves as a checkpoint in the control of endocrine cell equilibrium in pancreatic islets. Our data showed that SCD1 activity is essential for proper α-cell and β-cell lineage determination during morphogenesis of the pancreas and the maintenance of mature β-cell identity. The inhibition of SCD1 expression/activity led to both a decrease in the expression of β-cell signature genes (e.g., Pdx1, Nkx6.1, MafA, and Neurod1, among others) and induction of the expression of the dedifferentiation marker Sox9 in mature pancreatic islets. The transcriptional repression of Pdx1 and MafA in SCD1-deficient β-cells was related to the excessive methylation of promoter regions of these transcription factors. In contrast, SCD1 ablation favored the formation of α-cells over β-cells throughout pancreas organogenesis and did not compromise α-cell identity in adult pancreatic islets. Such molecular changes that were caused by SCD1 downregulation resulted in the mislocalization of α-cells within the core of islets and increased the ratio of pancreatic α- to β-cell mass. This was followed by islet dysfunction, including impairments in glucose-stimulated insulin release, simultaneously with elevations of basal glucagon secretion. Altogether, these findings provide additional mechanistic insights into the role of SCD1 in the pathogenesis of T2D. more...
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- 2023
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40. GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.
- Author
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Parik, Sweta, Fernández-García, Juan, Lodi, Francesca, De Vlaminck, Karen, Derweduwe, Marleen, De Vleeschouwer, Steven, Sciot, Raf, Geens, Wietse, Linqian Weng, Bosisio, Francesca Maria, Bergers, Gabriele, Duerinck, Johnny, De Smet, Frederick, Lambrechts, Diether, Van Ginderachter, Jo A., and Fendt, Sarah-Maria more...
- Subjects
FATTY acids ,TEMOZOLOMIDE ,SATURATED fatty acids ,GLIOBLASTOMA multiforme ,CANCER cells ,METHYLGUANINE - Abstract
Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
- Full Text
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41. Blood Lipid Responses to Diets Enriched with Cottonseed Oil Compared With Olive Oil in Adults with High Cholesterol in a Randomized Trial.
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Prater, M Catherine, Scheurell, Alexis R, Paton, Chad M, and Cooper, Jamie A
- Subjects
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HDL cholesterol , *TRIGLYCERIDES , *RESEARCH , *COTTONSEED oil , *HYPERCHOLESTEREMIA , *BLOOD sugar , *DIET , *EVALUATION research , *COMPARATIVE studies , *RANDOMIZED controlled trials , *RESEARCH funding , *CROSSOVER trials , *LIPIDS , *CHOLESTEROL - Abstract
Background: Increasing unsaturated fat intake is beneficial for cardiovascular health, but the type of unsaturated fat to recommend remains equivocal.Objectives: We investigated the effects of an 8-week diet intervention that was rich in either cottonseed oil (CSO; PUFA rich) or olive oil (OO; MUFA rich) on blood lipids in hypercholesterolemic adults.Methods: Forty-three men and women with hypercholesterolemia (53 ± 10 years; BMI, 27.6 ± 4.8 kg/m2) completed this randomized parallel clinical trial consisting of an 8-week partial outpatient feeding intervention. Participants were given meals and snacks accounting for ∼60% of their daily energy needs, with 30% of energy needs from either CSO (n = 21) or OO (n = 22). At pre- and postdiet intervention visits, participants consumed a high-SFA meal (35% of total energy needs; 70% of energy from fat). The primary outcomes of fasting cholesterol profiles and secondary outcomes of postprandial blood lipids and glycemic markers were assessed over a 5-hour period.Results: There were greater reductions from baseline to week 8 in fasting serum total cholesterol (TC; -17.0 ± 3.94 mg/dL compared with -2.18 ± 3.72 mg/dL, respectively; P = 0.008), LDL cholesterol (-19.7 ± 3.94 mg/dL compared with -5.72 ± 4.23 mg/dL, respectively; P = 0.018), non-HDL cholesterol (-20.8 mg/dL ± 4.00 compared with -6.61 ± 4.01 mg/dL, respectively; P = 0.014), and apoB (-11.8 mg/dL ± 2.37 compared with -3.10 ± 2.99 mg/dL, respectively; P = 0.05), in CSO compared with OO. There were also visit effects from baseline to week 8 for increases in HDL cholesterol (CSO, 56.5 ± 2.79 mg/dL to 60.2 ± 3.35 mg/dL, respectively; OO: 59.7 ± 2.63 mg/dL to 64.1 ± 2.24 mg/dL, respectively; P < 0.001), and decreases in the TC:HDL-cholesterol ratio (CSO, 4.30 ± 0.27 mg/dL to 3.78 ± 0.27 mg/dL, respectively; OO, 3.94 ± 0.16 mg/dL to 3.57 ± 0.11 mg/dL, respectively; P < 0.001), regardless of group assignment. In response to the high-SFA meal, there were differences in postprandial plasma glucose (P = 0.003) and triglyceride (P = 0.004) responses and a trend in nonesterified fatty acids (P = 0.11) between groups, showing protection in the postprandial state from an occasional high-SFA fat meal with CSO, but not OO, diet enrichment.Conclusions: CSO, but not OO, diet enrichment caused substantial improvements in fasting and postprandial blood lipids and postprandial glycemia in hypercholesterolemic adults. This trial was registered at clinicaltrials.gov as NCT04397055. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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42. Aspirin promotes RSL3-induced ferroptosis by suppressing mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutatnt colorectal cancer
- Author
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Hao Chen, Qinqin Qi, Nan Wu, Ying Wang, Qian Feng, Rong Jin, and Lei Jiang
- Subjects
Aspirin ,Ferroptosis ,mTOR ,SCD1 ,Colorectal cancer ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Ferroptosis, a new form of regulated cell death triggered by the iron-dependent peroxidation of phospholipids, is associated with cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. Aspirin is a widely used non-steroidal anti-inflammatory drug (NSAID) and has been reported to show therapeutic benefit in cancers harboring oncogenic PIK3CA, which encodes the catalytic p110α subunit of phosphoinositide 3-kinase (PI3K). In this study, we found that aspirin sensitized cancer cells harboring oncogenic activation of PIK3CA to ferroptosis induction. Mechanistically, aspirin inhibited protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, suppressed downstream sterol regulatory element-binding protein 1 (SREBP-1) expression, and attenuated stearoyl-CoA desaturase-1 (SCD1)-mediated lipogenesis of monounsaturated fatty acids, thus promoting RSL3-induced ferroptosis in colorectal cancer (CRC) cells. Moreover, genetic ablation of SREBP-1 or SCD1 conferred cancer cells greater sensitivity to ferroptosis induction. Conversely, ectopic expression of SREBP-1 or SCD1 restored ferroptosis resistance in CRC cells and abolished the effect of aspirin on RSL3-induced cytotoxicity. Additionally, the synergistic effects of aspirin and RSL3 were confirmed in a xenograft mouse model. The combined use of aspirin and RSL3 resulted in significant tumor suppression. Our work demonstrated that aspirin enhanced the cytotoxic effect of RSL3 in PIK3CA-mutant cancers, and the combination of aspirin and ferroptosis inducer displayed promising therapeutic effects in cancer treatment. more...
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- 2022
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43. GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide
- Author
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Sweta Parik, Juan Fernández-García, Francesca Lodi, Karen De Vlaminck, Marleen Derweduwe, Steven De Vleeschouwer, Raf Sciot, Wietse Geens, Linqian Weng, Francesca Maria Bosisio, Gabriele Bergers, Johnny Duerinck, Frederick De Smet, Diether Lambrechts, Jo A. Van Ginderachter, and Sarah-Maria Fendt more...
- Subjects
glioblastoma ,fatty acid metabolism ,lipotoxicity ,SCD1 ,FADS2 ,tumor heterogeneity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients. more...
- Published
- 2022
- Full Text
- View/download PDF
44. Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models
- Author
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Moreno,Nerea, Sabater-Arcis,Maria, Sevilla,Teresa, Alonso,Manuel Perez, Ohana,Jessica, Bargiela,Ariadna, Artero,Ruben, Moreno,Nerea, Sabater-Arcis,Maria, Sevilla,Teresa, Alonso,Manuel Perez, Ohana,Jessica, Bargiela,Ariadna, and Artero,Ruben more...
- Abstract
Background We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed. Results We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts. Conclusions For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype. more...
- Published
- 2024
45. A trans10-18:1 enriched fraction from beef fed a barley grain-based diet induces lipogenic gene expression and reduces viability of HepG2 cells
- Author
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Vahmani, Payam, Meadus, William J, da Silva, Maria LP, Mitchell, Alec D, Mapiye, Cletos, Duff, Pascale, Rolland, David C, and Dugan, Michael ER
- Subjects
Nutrition ,Biotechnology ,ACC ,acetyl-CoA carboxylase ,Ag+-SPE ,silver ion solid phase extraction ,BSA ,bovine serum albumin ,Beef ,Cell culture ,Cytotoxicity ,FAS ,fatty acid synthase ,Fatty acid metabolism ,HMGCR ,3-Hydroxy-3-Methylglutaryl-CoA reductase ,HT10 ,high-t10 fraction ,HT11 ,high-t11 fraction ,Liver ,MUFA ,monounsaturated fatty acids ,PHVO ,partially hydrogenated vegetable oils ,PL ,phospholipid ,PUFA ,polyunsaturated fatty acids ,SCD1 ,stearoyl-CoA desaturase-1 ,SFA ,saturated fatty acid ,SREBP1c ,sterol regulatory element-binding protein-1c ,SREBP2 ,sterol regulatory element-binding protein-2 ,TG ,triacylglycerol ,TLC ,thin layer chromatography ,Trans fatty acids ,c ,cis ,t ,trans ,Biochemistry and Cell Biology - Abstract
Beef fat is a natural source of trans (t) fatty acids, and is typically enriched with either t10-18:1 or t11-18:1. Little is known about the bioactivity of individual t-18:1 isomers, and the present study compared the effects of t9-18:1, cis (c)9-18:1 and trans (t)-18:1 fractions isolated from beef fat enriched with either t10-18:1 (HT10) or t11-18:1 (HT11). All 18:1 isomers resulted in reduced human liver (HepG2) cell viability relative to control. Both c9-18:1 and HT11were the least toxic, t9-18:1had dose response increased toxicity, and HT10 had the greatest toxicity (P more...
- Published
- 2016
46. Reduction of De Novo Lipogenesis Mediates Beneficial Effects of Isoenergetic Diets on Fatty Liver: Mechanistic Insights from the MEDEA Randomized Clinical Trial.
- Author
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Costabile, Giuseppina, Della Pepa, Giuseppe, Salamone, Dominic, Luongo, Delia, Naviglio, Daniele, Brancato, Valentina, Cavaliere, Carlo, Salvatore, Marco, Cipriano, Paola, Vitale, Marilena, Corrado, Alessandra, Rivellese, Angela Albarosa, Annuzzi, Giovanni, and Bozzetto, Lutgarda more...
- Abstract
Background: Non-alcoholic liver steatosis (NAS) results from an imbalance between hepatic lipid storage, disposal, and partitioning. A multifactorial diet high in fiber, monounsaturated fatty acids (MUFAs), n-6 and n-3 polyunsaturated fatty acids (PUFAs), polyphenols, and vitamins D, E, and C reduces NAS in people with type 2 diabetes (T2D) by 40% compared to a MUFA-rich diet. We evaluated whether dietary effects on NAS are mediated by changes in hepatic de novo lipogenesis (DNL), stearoyl-CoA desaturase (SCD1) activity, and/or β-oxidation. Methods: According to a randomized parallel group study design, 37 individuals with T2D completed an 8-week isocaloric intervention with a MUFA diet (n = 20) or multifactorial diet (n = 17). Before and after the intervention, liver fat content was evaluated by proton magnetic resonance spectroscopy, serum triglyceride fatty acid concentrations measured by gas chromatography, plasma β-hydroxybutyrate by enzymatic method, and DNL and SCD-1 activity assessed by calculating the palmitic acid/linoleic acid (C16:0/C18:2 n6) and palmitoleic acid/palmitic acid (C16:1/C16:0) ratios, respectively. Results: Compared to baseline, mean ± SD DNL significantly decreased after the multifactorial diet (2.2 ± 0.8 vs. 1.5 ± 0.5, p = 0.0001) but did not change after the MUFA diet (1.9 ± 1.1 vs. 1.9 ± 0.9, p = 0.949), with a significant difference between the two interventions (p = 0.004). The mean SCD-1 activity also decreased after the multifactorial diet (0.13 ± 0.05 vs. 0.10 ± 0.03; p = 0.001), but with no significant difference between interventions (p = 0.205). Fasting plasma β-hydroxybutyrate concentrations did not change significantly after the MUFA or multifactorial diet. Changes in the DNL index significantly and positively correlated with changes in liver fat (r = 0.426; p = 0.009). Conclusions: A diet rich in multiple beneficial dietary components (fiber, polyphenols, MUFAs, PUFAs, and other antioxidants) compared to a diet rich only in MUFAs further reduces liver fat accumulation through the inhibition of DNL. Registered under ClinicalTrials.gov no. NCT03380416. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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47. Long noncoding RNA LINC01606 protects colon cancer cells from ferroptotic cell death and promotes stemness by SCD1–Wnt/β‐catenin–TFE3 feedback loop signalling.
- Author
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Luo, Yajun, Huang, Siqi, Wei, Jinlai, Zhou, He, Wang, Wuyi, Yang, Jianguo, Deng, Qican, Wang, Hao, and Fu, Zhongxue
- Subjects
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WNT signal transduction , *COLON cancer , *LINCRNA , *CELL death , *CANCER cells , *GAS chromatography/Mass spectrometry (GC-MS) , *CANCER cell growth , *REACTIVE oxygen species - Abstract
Background: Ferroptosis is principally caused by iron catalytic activity and intracellular lipid peroxidation. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis. However, the potential interplay between lncRNA LINC01606 and ferroptosis in colon cancer remains elusive. Methods: The expression level of LNC01606 in colon cancer tissue was detected by quantitative real‐time polymerase chain reaction. The functional role of LNC01606 was investigated by gain‐ and loss‐of‐function assays both in vitro and in vivo. The LINC01606‐SCD1‐Wnt/β‐catenin‐TFE3 axis were screened and validated by DNA/RNA pull down, gas chromatography‐mass spectrometry, RNA immunoprecipitation and dual‐luciferase reporter. Results: The expression of lncRNA LINC01606 was frequently upregulated in human colon cancer and strongly associated with a poor prognosis. LINC01606 functioned as an oncogene and promotes colon cancer cell growth, invasion and stemness both in vitro and in vivo. Moreover, LINC01606 protected colon cancer cells from ferroptosis by decreasing the concentration of iron, lipid reactive oxygen species, mitochondrial superoxide and increasing mitochondrial membrane potential. Mechanistically, LINC01606 enhanced the expression of stearoyl‐CoA desaturase 1 (SCD1), serving as a competing endogenous RNA to modulate miR‐423‐5p expression, subsequently activating the canonical Wnt/β‐catenin signaling, and transcription factor binding to IGHM enhancer 3 (TFE3) increased LINC01606 transcription after recruitment to the promoter regions of LINC01606. Furthermore, we confirmed that upregulated LINC01606 and Wnt/β‐catenin formed a positive feedback regulatory loop, further inhibiting ferroptosis and enhancing stemness. Conclusions: LINC01606 functions as an oncogene to facilitate tumor cell stemness, proliferation and inhibit ferroptosis and is a promising therapeutic target for colon cancer. [ABSTRACT FROM AUTHOR] more...
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- 2022
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48. The effects of endurance training and estrogen-related receptor α disruption on mitofusin 1 and 2, GLUT2, PPARβ/δ and SCD1 expression in the liver of diabetic rats
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B. Shahouzehi, Y. Masoumi-Ardakani, H. Fallah, and S. Aminizadeh
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diabetes ,estrogen related receptor alpha (errα) ,glut2 ,mitofusin ,pparδ ,scd1 ,Biochemistry ,QD415-436 ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Diabetes is a progressive and metabolic disease with a high prevalence throughout the world. Physical activity is considered as an intervention to improve diabetes. Intervention such as estrogen-related receptor α (ERRα) inhibition is considered as a new way to manage diabetes. In current study, we examined ERRα inhibition along with exercise training (ET) on the gene expression of mitofusin 1 (MFN1), MFN2, glucose transporter 2 (GLUT2), peroxisome proliferator-activated receptor beta or delta (PPARβ/δ), and stearoyl-CoA desaturase 1 (SCD1) in rat liver. The animals were divided into 8 groups (n = 7); 1, Control (CTL) 2, Diabetes (D) 3, ERRα inhibition (ERRI) 4, Endurance Training (ET) 5, Diabetes+ERRα inhibition (D+ERRI) 6, Diabetes+Endurance training (D+ET) 7, Endurance Training +ERRα inhibition (ET+ERRI) 8, Diabetes+Endurance Training+ERRα inhibition (D+ET+ERRI). The liver tissues were used for Real-Time PCR. The results showed that ET significantly increased PPARδ, MFN1 and, MFN2 expression in control rats compared to DM group. In ERRI group, SCD1, GLUT2, MFN1 and MFN2 gene expression was increased compared to CTL and D group. In CTL and D rats, the combination of ERRα inhibition and ET significantly and additively increased MFN1, MFN2, and GLUT2 expression. Overall, the combination of ET and ERRα inhibition probably can be considered as a potential therapeutic intervention for treatment of metabolic diseases including diabetes and cardiovascular disease. more...
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- 2020
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49. Sexual Selection Does Not Increase the Rate of Compensatory Adaptation to a Mutation Influencing a Secondary Sexual Trait in Drosophila melanogaster
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Christopher H. Chandler, Anna Mammel, and Ian Dworkin
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sex comb ,sex combs distal ,scd1 ,deleterious mutation ,drosophila ,compensatory evolution ,sexual selection ,natural selection ,Genetics ,QH426-470 - Abstract
Theoretical work predicts that sexual selection can enhance natural selection, increasing the rate of adaptation to new environments and helping purge harmful mutations. While some experiments support these predictions, remarkably little work has addressed the role of sexual selection on compensatory adaptation—populations’ ability to compensate for the costs of deleterious alleles that are already present. We tested whether sexual selection, as well as the degree of standing genetic variation, affect the rate of compensatory evolution via phenotypic suppression in experimental populations of Drosophila melanogaster. These populations were fixed for a spontaneous mutation causing mild abnormalities in the male sex comb, a structure important for mating success. We fine-mapped this mutation to an ∼85 kb region on the X chromosome containing three candidate genes, showed that the mutation is deleterious, and that its phenotypic expression and penetrance vary by genetic background. We then performed experimental evolution, including a treatment where opportunity for mate choice was limited by experimentally enforced monogamy. Although evolved populations did show some phenotypic suppression of the morphological abnormalities in the sex comb, the amount of suppression did not depend on the opportunity for sexual selection. Sexual selection, therefore, may not always enhance natural selection; instead, the interaction between these two forces may depend on additional factors. more...
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- 2020
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50. Fatty acid profile and estimated desaturase activities in whole blood are associated with metabolic health
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Karianne Svendsen, Thomas Olsen, Tove C. Nordstrand Rusvik, Stine M. Ulven, Kirsten B. Holven, Kjetil Retterstøl, and Vibeke H. Telle-Hansen
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Fatty acids ,Desaturases ,Obesity ,Metabolic disease ,Stearoyl CoA desaturase ,SCD1 ,Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
Abstract Background The aim was to investigate if fatty acid profile and estimated desaturase activities; stearoyl CoA-desaturase (SCD), delta-5-desaturase and delta-6-desaturase (D5D; D6D), differ between individuals with metabolically healthy (MH) and unhealthy (MU) phenotypes. We also explored these associations according to BMI categories. Methods Men and women at moderately elevated risk of cardiovascular disease were included in this cross-sectional study (n = 321). If subjects met ≥4 out of 5 criteria (elevated triglycerides, total and LDL-cholesterol, HbA1c and low HDL-cholesterol), they were classified as MU (n = 52). If levels were within reference ranges for ≥3 of the same criteria, subjects were classified as MH (n = 150). Utilizing the entire population, a score ranging from 0 to 5 denoting the number of MU criteria met was computed. Estimated desaturase activities were calculated as product-to-precursor ratio of fatty acids in whole blood (SCD16 [16:1n7/16:0], SCD18 [18:1n9/18:0], D5D [18:3n6/18:2n6], D6D [20:4n6/20:3n6]). Results Individuals with MH had lower estimated SCD16 and SCD18 activities, whereas estimated D6D activity was higher compared to MU. Similar, SCD16 and SCD18 increased, whereas D6D decreased with increasing criteria of MU. Trends were similar across BMI categories. Conclusions This study supports the notion of estimated desaturase activities as possible novel biomarkers of metabolic health irrespectively of BMI. more...
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- 2020
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