Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Abstract

Long chain acyl-CoA synthetases (ACSL) and fatty acid transport proteins (FATP) activate fatty acids to acyl-CoAs in the initial step of fatty acid metabolism. Numerous isoforms of ACSL and FATP exist with different tissue distribution patterns, intracellular locations, and substrate preferences, suggesting that each isoform has distinct functions in channeling fatty acids into different metabolic pathways. Because fatty acids, acyl-CoAs, and downstream lipid metabolites regulate various transcription factors that control hepatic energy metabolism, we hypothesized that ACSL or FATP isoforms differentially regulate hepatic gene expression. Using small interference RNA (siRNA), we knocked down each liver-specific ACSL and FATP isoform in rat primary hepatocyte cultures and subsequently analyzed reporter gene activity of numerous transcription factors and performed quantitative mRNA analysis of their target genes. Compared with control cells, which were transfected with control siRNA, knockdown of acyl-CoA synthetase 3 (ACSL3) significantly decreased reporter gene activity of several lipogenic transcription factors such as peroxisome proliferator activation receptor-γ, carbohydrate-responsive element-binding protein, sterol regulatory element-binding protein-1c, and liver X receptor-α and the expression of their target genes. These findings were further supported by metabolic labeling studies that showed [1-14C]acetate incorporation into lipid extracts was decreased in cells treated with ACSL3 siRNAs and that ACSL3 expression is up-regulated in ob/ob mice and mice fed a high sucrose diet. ACSL3 knockdown decreased total acyl-CoA synthetase activity without substantially altering the expression of other ACSL isoforms. In summary, these results identify a novel role for ACSL3 in mediating transcriptional control of hepatic lipogenesis. Long chain acyl-CoA synthetases (ACSL) and fatty acid transport proteins (FATP) activate fatty acids to acyl-CoAs in the initial step of fatty acid metabolism. Numerous isoforms of ACSL and FATP exist with different tissue distribution patterns, intracellular locations, and substrate preferences, suggesting that each isoform has distinct functions in channeling fatty acids into different metabolic pathways. Because fatty acids, acyl-CoAs, and downstream lipid metabolites regulate various transcription factors that control hepatic energy metabolism, we hypothesized that ACSL or FATP isoforms differentially regulate hepatic gene expression. Using small interference RNA (siRNA), we knocked down each liver-specific ACSL and FATP isoform in rat primary hepatocyte cultures and subsequently analyzed reporter gene activity of numerous transcription factors and performed quantitative mRNA analysis of their target genes. Compared with control cells, which were transfected with control siRNA, knockdown of acyl-CoA synthetase 3 (ACSL3) significantly decreased reporter gene activity of several lipogenic transcription factors such as peroxisome proliferator activation receptor-γ, carbohydrate-responsive element-binding protein, sterol regulatory element-binding protein-1c, and liver X receptor-α and the expression of their target genes. These findings were further supported by metabolic labeling studies that showed [1-14C]acetate incorporation into lipid extracts was decreased in cells treated with ACSL3 siRNAs and that ACSL3 expression is up-regulated in ob/ob mice and mice fed a high sucrose diet. ACSL3 knockdown decreased total acyl-CoA synthetase activity without substantially altering the expression of other ACSL isoforms. In summary, these results identify a novel role for ACSL3 in mediating transcriptional control of hepatic lipogenesis. Intracellular fatty acids and downstream metabolites affect a host of physiological processes, including transcriptional control of energy metabolism (1Mashek D.G. Li L.O. Coleman R.A. Future Lipidol. 2007; 2: 465-476Crossref PubMed Scopus (174) Google Scholar, 2Jump D.B. Botolin D. Wang Y. Xu J. Christian B. Demeure O. J. Nutr. 2005; 135: 2503-2506Crossref PubMed Scopus (376) Google Scholar). Fatty acids and/or their metabolites regulate hepatic transcription factors such as peroxisome proliferator activation receptors (PPARs), 2The abbreviations used are: PPARperoxisome proliferator-activated receptorACCacetyl-CoA carboxylaseACSLlong chain acyl-CoA synthetaseAMPKAMP kinaseChREBPcarbohydrate-responsive element-binding proteinFASfatty acid synthaseFATPfatty acid transport proteinsLXRliver X receptorPGC-1βPPAR-γ co-activator-1βSREBPsterol regulatory element-binding proteinsiRNAsmall interference RNARTreverse transcriptionTAGtriacylglycerol. carbohydrate-responsive element-binding protein (ChREBP), sterol regulatory element-binding protein (SREBP)-1c, and liver X receptor (LXR)-α (3Zhang Y.L. Hernandez-Ono A. Siri P. Weisberg S. Conlon D. Graham M.J. Crooke R.M. Huang L.S. Ginsberg H.N. J. Biol. Chem. 2006; 281: 37603-37615Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 4Pawar A. Xu J. Jerks E. Mangelsdorf D.J. Jump D.B. J. Biol. 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These polyunsaturated fatty acids also suppress activity of ChREBP, SREBP-1c, and LXR-α through multiple mechanisms (2Jump D.B. Botolin D. Wang Y. Xu J. Christian B. Demeure O. J. Nutr. 2005; 135: 2503-2506Crossref PubMed Scopus (376) Google Scholar, 4Pawar A. Xu J. Jerks E. Mangelsdorf D.J. Jump D.B. J. Biol. Chem. 2002; 277: 39243-39250Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 5Xu J. Teran-Garcia M. Park J.H. Nakamura M.T. Clarke S.D. J. Biol. Chem. 2001; 276: 9800-9807Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 9Dentin R. Benhamed F. Pégorier J.P. Foufelle F. Viollet B. Vaulont S. Girard J. Postic C. J. Clin. Investig. 2005; 115: 2843-2854Crossref PubMed Scopus (241) Google Scholar, 10Lorente-Cebrián S. Pérez-Matute P. Martínez J.A. Marti A. Moreno-Aliaga M.J. J. Physiol. Biochem. 2006; 62: 61-69Crossref PubMed Google Scholar), whereas saturated fatty acids activate SREBP-1c by recruiting the SREBP-1c co-activator, PPAR-γ co-activator-1β (PGC-1β) (2Jump D.B. Botolin D. Wang Y. Xu J. Christian B. Demeure O. J. Nutr. 2005; 135: 2503-2506Crossref PubMed Scopus (376) Google Scholar,11Lin J. Yang R. Tarr P.T. Wu P.H. Handschin C. Li S. Yang W. Pei L. Uldry M. Tontonoz P. Newgard C.B. Spiegelman B.M. Cell. 2005; 120: 261-273Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar). Also intracellular fatty acids derived from de novo lipogenesis or hydrolysis of triacylglycerol (TAG) or phospholipid can activate these transcription factors. For example, recent evidence suggests that modulating specific pathways, such as de novo fatty acid synthesis or TAG hydrolysis, which supply intracellular fatty acids, regulates gene expression (12Chakravarthy M.V. Pan Z. Zhu Y. Tordjman K. Schneider J.G. Coleman T. Turk J. Semenkovich C.F. Cell Metab. 2005; 1: 309-322Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 13Sapiro J.M. Mashek M.T. Greenberg A.S. Mashek D.G. J. Lipid Res. 2009; 50: 1621-1629Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Such evidence that different regulation of these transcription factors by fatty acid type (unsaturated versus saturated) or source (intracellular versus exogenous) implicates that certain proteins or enzymes that control cellular uptake or trafficking of fatty acids and their downstream metabolites could mediate their effects on gene expression. peroxisome proliferator-activated receptor acetyl-CoA carboxylase long chain acyl-CoA synthetase AMP kinase carbohydrate-responsive element-binding protein fatty acid synthase fatty acid transport proteins liver X receptor PPAR-γ co-activator-1β sterol regulatory element-binding protein small interference RNA reverse transcription triacylglycerol. Acyl-CoA synthetase (ACSL) and fatty acid transport protein (FATP) activate fatty acids to acyl-CoAs in the presence of ATP and CoA. After this initial step, acyl-CoAs enter multiple metabolic pathways for lipid synthesis or β-oxidation (1Mashek D.G. Li L.O. Coleman R.A. Future Lipidol. 2007; 2: 465-476Crossref PubMed Scopus (174) Google Scholar, 14Mashek D.G. Coleman R.A. Curr. Opin. Lipidol. 2006; 17: 274-278Crossref PubMed Scopus (118) Google Scholar). FATP, also termed very long chain acyl-CoA synthetase, share 20–40% of sequence similarity with ACSL and have substrate very long chain fatty acids also activity long chain fatty acids (1Mashek D.G. Li L.O. Coleman R.A. Future Lipidol. 2007; 2: 465-476Crossref PubMed Scopus (174) Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of these enzymes has several isoforms that have cellular patterns, substrate preferences, and (1Mashek D.G. Li L.O. Coleman R.A. Future Lipidol. 2007; 2: 465-476Crossref PubMed Scopus (174) Google Scholar, 14Mashek D.G. Coleman R.A. Curr. Opin. Lipidol. 2006; 17: 274-278Crossref PubMed Scopus (118) Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.G. Li L.O. Coleman R.A. J. Lipid Res. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). or studies also for the ACSL and FATP isoforms in fatty acid of in rat primary results in channeling of acid and phospholipid synthesis and from L.O. Mashek D.G. J. S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). of ACSL3 in acid incorporation to for very synthesis J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google role in energy metabolism. of in rat fatty acid incorporation into TAG with substrate fatty acids, fatty acids, and without in β-oxidation or phospholipid synthesis D.G. Coleman R.A. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). channeling of fatty acids into metabolic pathways that ACSL and FATP isoforms regulate distinct of intracellular on the regulation of ACSL or FATP enzymes on fatty acid channeling and the of fatty acids or their downstream metabolites on transcription factors involving energy metabolism, we hypothesized that or FATP isoforms differentially regulate hepatic gene expression. the of this was to which ACSL or FATP isoforms are for modulating the activity of transcription factors in hepatic energy metabolism by the ACSL or FATP isoforms in the that ACSL3 cells PPAR-γ that knockdown of ACSL3 decreased the activity of several lipogenic transcription their target gene and of de novo lipogenesis. we that ACSL3 hepatic lipogenesis through transcriptional regulation of gene expression. were from and were from was from acid was from or expression and a reporter were by and expression and reporter were by Mangelsdorf of For the reporter and expression were by Towle of and for the sequence on the gene and the expression which a of SREBP-1c, were by of and were from other were from were on a and were to hepatocyte were by the A.K. Towle H.C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), and as by was were a of in and were by the of and of ACSL or FATP isoforms were by and are in sequence siRNA, which was by as a was transfected into primary with of cells cells were were and by with and of for ACSL or FATP in a were with the or expression and a reporter cells for PPAR-γ and PPAR-α expression and reporter was used for of For and reporter by and the sequence on the gene were transfected in cells for reporter gene For of and and expression were used was used a of cells as control for of each reporter gene were for reporter gene and activity of each transcription was as RNA was with and was with the reverse and were with and to the on sequence were for with of for each gene are in were analyzed the and the mRNA of each gene was to for quantitative reverse TAG in a For protein expression of ACSL3 and AMP kinase were and in and of total proteins were for in and were by a and to a of proteins was by After the was in in with and with ACSL3 or The were by with a transfected with control or ACSL siRNAs were with and in and and on with of a tissue were were determined by the Acyl-CoA synthetase specific activity was determined by the of in the presence of and in The was performed in a total of for The was by of protein, with of and fatty acids were with to of the the or were with of and of acid for or 3 as in the were with in and cellular were J. Biochem. Physiol. PubMed Scopus Google Scholar). of the lipid extracts from the cells were by on in acid with lipid and in The in of the total lipid extracts and from were or were J. Biochem. Physiol. PubMed Scopus Google and total intracellular fatty acids were by on in acid fatty acids were in 3 for The fatty acids were with and to analysis S.D. PubMed Scopus (241) Google Scholar). were as of were by studies were to a of to each ACSL or FATP gene in liver for knockdown of of each ACSL and FATP mRNA was with control cells by of the siRNAs we the of siRNA, we these siRNAs in rat primary with reporter gene for PPAR-γ or the different ACSL or FATP ACSL3 significantly and PPAR-γ activity with control cells of the ACSL or FATP siRNAs reporter gene activity of PPAR-α these we to further the role of ACSL3 in modulating hepatic gene expression to control energy metabolism. that the of the ACSL3 was to we ACSL3 a different of ACSL3 mRNA and that the of ACSL3 mRNA was by in cells transfected with ACSL3 different of the ACSL3 gene ACSL3 siRNAs also decreased the of ACSL3 protein expression we other ACSL or FATP isoforms expression in to knockdown of this mRNA of each ACSL or FATP isoform was analyzed in ACSL3 cells of which is the that the protein of ACSL3 is the expression of mRNA was up-regulated in cells transfected with of the ACSL3 the of the other ACSL or FATP isoforms were significantly by the expression of ACSL3 These that the expression of the other isoforms of ACSL or FATP for a of of ACSL3 siRNAs decreased total acyl-CoA synthetase activity and with control we for the ACSL3 siRNA, the ACSL3 also PPAR-γ activity by of ACSL3 the activity of lipogenic transcription factors in rat primary or were transfected in rat primary and reporter gene were and for reporter of sequence on gene were transfected for reporter gene in were also transfected with a of and reporter by the was transfected for of in cells treated with and and expression were with reporter in cells treated with or for to and expression and reporter were used for of LXR-α activity in cells treated with or for are from a performed in that was or with of PPAR-γ has in (2Jump D.B. Botolin D. Wang Y. Xu J. Christian B. Demeure O. J. Nutr. 2005; 135: 2503-2506Crossref PubMed Scopus (376) Google Scholar, Z. T. Wang Z. M. Li J. J. Physiol. Metab. 2004; PubMed Scopus Google Scholar), this transcription has also to lipogenesis and lipid in liver (3Zhang Y.L. Hernandez-Ono A. Siri P. Weisberg S. Conlon D. Graham M.J. Crooke R.M. Huang L.S. Ginsberg H.N. J. Biol. Chem. 2006; 281: 37603-37615Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, B.M. J. Physiol. Metab. 2005; PubMed Scopus Google Scholar, J. M. T. P. J. A. R.M. 2007; PubMed Scopus Google Scholar). on initial findings that PPAR-γ was by ACSL3 we to further ACSL3 other transcription factors such as SREBP-1c, and ChREBP, of which to the regulation of lipogenic gene expression. ACSL3 siRNAs decreased reporter gene activity of and and LXR-α and and The reporter gene activity for were performed with reporter sterol regulatory was or were we the of SREBP-1c in in with reporter ACSL3 of reporter gene activity was by of SREBP-1c is to the primary transcription that the expression of and lipogenic genes A.K. Ma L. Towle H.C. J. Biol. Chem. 2004; 279: 15662-15669Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 9Dentin R. Benhamed F. Pégorier J.P. Foufelle F. Viollet B. Vaulont S. Girard J. Postic C. J. Clin. Investig. 2005; 115: 2843-2854Crossref PubMed Scopus (241) Google Scholar). to the other lipogenic transcription ACSL3 knockdown reporter gene activity we the cells with high to ACSL3 siRNAs high and the in activity to high control cells a in activity in to high whereas cells with ACSL3 expression with a to ACSL3 to activity and for these transcription factors can PPAR-γ or LXR-α activity in cells transfected with ACSL3 siRNA, we cells with or for PPAR-γ and to these PPAR-γ or LXR-α activity and these were to PPAR-γ or LXR-α activity in to ACSL3 Because the reporter gene showed that ACSL3 the activity of numerous transcription factors involving we determined the expression of lipogenic genes was in to ACSL3 Compared with control cells, ACSL3 siRNAs the expression of numerous genes in fatty acid metabolism including and with a for decreased and the expression of a target gene of was also the expression of the transcription factors ChREBP, SREBP-1c, and PPAR-γ were Because showed the in activity ACSL3 we also analyzed protein expression of to the that protein were by ACSL3 with mRNA the of protein was ACSL3 knockdown These that the of lipogenic gene expression by ACSL3 knockdown was to the transcriptional activity of these transcription factors in their expression. is to several lipogenic transcription factors J. Yang R. Tarr P.T. Wu P.H. Handschin C. Li S. Yang W. Pei L. Uldry M. Tontonoz P. Newgard C.B. Spiegelman B.M. Cell. 2005; 120: 261-273Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, C. Cell Metab. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar), is that ACSL3 have as a to lipogenic gene expression. we in expression these that ACSL3 lipogenic gene expression through transcriptional activity in expression of the transcription factors or a The results that ACSL3 has a role in modulating the expression of lipogenic genes. the of hepatic lipogenic gene expression by ACSL3 knockdown to of cells were with and the of acid to total was Compared with cells transfected with the control siRNA, incorporation of acid into total was by in ACSL3 cells of into different of and was also decreased to a These that the decreased expression of lipogenic genes results in decreased of de novo lipogenesis. of de novo lipogenesis acid which is of of fatty acid derived from de novo lipogenesis lipid was also decreased in ACSL3 cells and ACSL3 knockdown decreased of de novo fatty acid synthesis in with the in lipogenic gene expression. further analyzed the of intracellular fatty acids to ACSL3 knockdown their and in ACSL3 cells fatty acids and a in saturated fatty acid with control cells The saturated fatty acids and were ACSL3 knockdown and the of fatty acids In several polyunsaturated fatty acids were decreased in to is a energy in cells that regulates numerous transcription including of the lipogenic transcription factors by ACSL3 knockdown D.G. J. Physiol. 277: Google Scholar). The ACSL enzymes the of of ATP and the which studies have that the acyl-CoA synthetase activity a role in altering activation M.S. J.M. A.K. Greenberg A.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ACSL3 knockdown could which is to regulate numerous transcription factors to control gene expression M. Y. M. M. K. M. R. M. Res. PubMed Scopus Google Scholar, T. K. T. K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). total of were by ACSL3 knockdown that the effects of ACSL3 on lipogenesis were through from the with on ACSL3 J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. T. J. M. S. M. Y. A. T. J. Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, G. L. Wang R. J. Biol. 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Because that ACSL3 de novo lipogenesis through transcriptional ACSL3 a target for in liver energy metabolism in numerous metabolic findings that ACSL3 transcriptional control of hepatic energy metabolism, the mechanisms of ACSL3 these effects are were to transcriptional activity of and PPAR-γ suggesting that ACSL3 regulates transcriptional control a a role for in mediating the effects of ACSL3 on gene expression. of the intracellular fatty acid that ACSL3 knockdown the of saturated fatty acids and decreased polyunsaturated fatty saturated fatty acids have to lipogenesis J. Yang R. Tarr P.T. Wu P.H. Handschin C. Li S. Yang W. Pei L. Uldry M. Tontonoz P. Newgard C.B. Spiegelman B.M. Cell. 2005; 120: 261-273Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar), whereas polyunsaturated fatty acids are of lipogenic gene expression M.T. Y. Li Y. 2004; PubMed Scopus Google Scholar). is that in specific fatty acids can the effects of ACSL3 knockdown on hepatic gene expression. Because ACSL3 knockdown in decreased activity of the lipogenic transcription factors is to that a or is by in a specific of metabolites as a of ACSL3 is also that ACSL3 through the effects on gene expression. of the role of ACSL3 in lipid and channeling further into the mediating In we for the that ACSL3 regulates lipogenic transcription factors to control hepatic energy metabolism. which are in with other studies that intracellular and fatty acid trafficking have a regulatory role in lipid metabolism through transcriptional regulation (1Mashek D.G. Li L.O. Coleman R.A. Future Lipidol. 2007; 2: 465-476Crossref PubMed Scopus (174) Google Scholar, M. A. C. M. G. R. Z. J.G. PubMed Scopus Google Scholar, F. Huang A. D. PubMed Scopus Google Scholar), that ACSL3 have role in lipogenesis the of hepatic and