PPARδ activation induces hepatic long-chain acyl-CoA synthetase 4 expression in vivo and in vitro (original) (raw)
2015, Biochimica et biophysica acta
a b s t r a c t The arachidonic acid preferred long-chain acyl-CoA synthetase 4 (ACSL4) is a key enzyme for fatty acid metabo-20 lism in various metabolic tissues. In this study, we utilized hamsters fed a normal chow diet, a high-fat diet or a 21 high cholesterol and high fat diet (HCHFD) as animal models to explore novel transcriptional regulatory mecha-22 nisms for ACSL4 expression under hyperlipidemic conditions. Through cloning hamster ACSL4 homolog and tis-23 sue profiling ACSL4 mRNA and protein expressions we observed a selective upregulation of ACSL4 in testis and 24 liver of HCHFD fed animals. Examination of transcriptional activators of the ACSL family revealed an increased he-25 patic expression of PPARδ but not PPARα in HCHFD fed hamsters. To explore a role of PPARδ in dietary 26 cholesterol-mediated upregulation of ACSL4, we administered a PPARδ specific agonist L165041 to normolipide-27 mic and dyslipidemic hamsters. We observed significant increases of hepatic ACSL4 mRNA and protein levels in 28 all L165041-treated hamsters as compared to control animals. The induction of ACSL4 expression by L165041 in 29 liver tissue in vivo was recapitulated in human primary hepatocytes and hepatocytes isolated from hamster and 30 mouse. Moreover, employing the approach of adenovirus-mediated gene knockdown, we showed that depletion 31 of PPARδ in hamster hepatocytes specifically reduced ACSL4 expression. Finally, utilizing HepG2 as a model sys-32 tem, we demonstrate that PPARδ activation leads to increased ACSL4 promoter activity, mRNA and protein ex-33 pression, and consequently higher arachidonoyl-CoA synthetase activity. Taken together, we have discovered a 34 novel PPARδ-mediated regulatory mechanism for ACSL4 expression in liver tissue and cultured hepatic cells. 35 © 2015 Published by Elsevier B.V. 36 37 38 39 40 65 of ACSL4 in rat smooth muscle cell inhibited IL-1β induced PGE2 secre-66 tion [14]. In breast cancer cells exogenous expression of ACSL4 promot-67 ed the cell invasiveness by regulating AA availability for enzymes such 68 as COX, LOX and CYP450s to generate eicosanoids [15]. In pancreatic 69 cell lines, diminished ACSL4 expression by siRNA mediated knockdown 70 reduces glucose-stimulated insulin secretion [16]. Studies also have 71 shown ACSL4 being capable of channeling fatty acid towards phos-72
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