title: PPARδ activation induces hepatic long-chain acyl-CoA synthetase 4 expression in vivo and in vitro.
abstract: The arachidonic acid preferred long-chain acyl-CoA synthetase 4 (ACSL4) is a key enzyme for fatty acid metabolism in various metabolic tissues. In this study, we utilized hamsters fed a normal chow diet, a high-fat diet or a high cholesterol and high fat diet (HCHFD) as animal models to explore novel transcriptional regulatory mechanisms for ACSL4 expression under hyperlipidemic conditions. Through cloning hamster ACSL4 homolog and tissue profiling ACSL4 mRNA and protein expressions we observed a selective upregulation of ACSL4 in testis and liver of HCHFD fed animals. Examination of transcriptional activators of the ACSL family revealed an increased hepatic expression of PPARδ but not PPARα in HCHFD fed hamsters. To explore a role of PPARδ in dietary cholesterol-mediated upregulation of ACSL4, we administered a PPARδ specific agonist L165041 to normolipidemic and dyslipidemic hamsters. We observed significant increases of hepatic ACSL4 mRNA and protein levels in all L165041-treated hamsters as compared to control animals. The induction of ACSL4 expression by L165041 in liver tissue in vivo was recapitulated in human primary hepatocytes and hepatocytes isolated from hamster and mouse. Moreover, employing the approach of adenovirus-mediated gene knockdown, we showed that depletion of PPARδ in hamster hepatocytes specifically reduced ACSL4 expression. Finally, utilizing HepG2 as a model system, we demonstrate that PPARδ activation leads to increased ACSL4 promoter activity, mRNA and protein expression, and consequently higher arachidonoyl-CoA synthetase activity. Taken together, we have discovered a novel PPARδ-mediated regulatory mechanism for ACSL4 expression in liver tissue and cultured hepatic cells.
authors: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States.
authors: Chin Fung Kelvin
authors: CF
authors: Kan
authors: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States.
authors: Amar Bahadur
authors: AB
authors: Singh
authors: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States.
authors: Bin
authors: B
authors: Dong
authors: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States; Department of Medicine, Stanford University, Stanford, CA 94305, United States.
authors: Vikram Ravindra
authors: VR
authors: Shende
authors: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States. Electronic address: Jingwen.Liu@va.gov.
authors: Jingwen
authors: J
authors: Liu
mesh_terms: D000818:Animals; D002791:Cholesterol, Dietary / Q000378:metabolism; D003001:Cloning, Molecular; D003066:Coenzyme A Ligases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004790:Enzyme Induction; D020869:Gene Expression Profiling / Q000379:methods; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006949:Hyperlipidemias / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008647:Mesocricetus; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010642:Phenoxyacetates / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D013737:Testis / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D002791:Cholesterol, Dietary; D047495:PPAR gamma; D010642:Phenoxyacetates; D012333:RNA, Messenger; C581020:Acsl4 protein, mouse; D003066:Coenzyme A Ligases; C033896:arachidonate - CoA ligase; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
keywords: ACSL4; Dietary cholesterol; Dyslipidemia; Hamsters; NAFLD; PPARδ
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