Liver-specific Loss of Long Chain Acyl-CoA Synthetase-1 Decreases Triacylglycerol Synthesis and β-Oxidation and Alters Phospholipid Fatty Acid Composition
In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping preferences for fatty acid chain length and saturation and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25–35% decrease in long chain acyl-CoA content. Although the content of triacylglycerol was unchanged in Acsl1L−/− liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the incorporation of [14C]oleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition, decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from [14C]oleate suggested that hepatic ACSL1 is important for mitochondrial β-oxidation of long chain fatty acids. Because the Acsl1L−/− mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates is insufficient to protect against hepatic insulin resistance. In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping preferences for fatty acid chain length and saturation and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25–35% decrease in long chain acyl-CoA content. Although the content of triacylglycerol was unchanged in Acsl1L−/− liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the incorporation of [14C]oleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition, decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from [14C]oleate suggested that hepatic ACSL1 is important for mitochondrial β-oxidation of long chain fatty acids. Because the Acsl1L−/− mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates is insufficient to protect against hepatic insulin resistance. Acyl-CoA synthetase (ACSL) 3The abbreviations used are: ACSLlong chain acyl-CoA synthetaseAGPATacylglycerol-3-phosphate acyltransferaseANOVAanalysis of varianceASMacid-soluble metaboliteCEcholesteryl esterDAGdiacylglycerolFAfatty acidFATPfatty acid transport proteinGPATglycerol-3-phosphate acyltransferaseITTinsulin tolerance testLPAlysophosphatidic acidLPClysophosphatidylcholineneoneomycinOGTToral glucose tolerance testPCphosphatidylcholinePEphosphatidylethanolaminePSphosphatidylserinePPARperoxisome proliferator-activated factorTAGtriacylglycerol. 3The abbreviations used are: ACSLlong chain acyl-CoA synthetaseAGPATacylglycerol-3-phosphate acyltransferaseANOVAanalysis of varianceASMacid-soluble metaboliteCEcholesteryl esterDAGdiacylglycerolFAfatty acidFATPfatty acid transport proteinGPATglycerol-3-phosphate acyltransferaseITTinsulin tolerance testLPAlysophosphatidic acidLPClysophosphatidylcholineneoneomycinOGTToral glucose tolerance testPCphosphatidylcholinePEphosphatidylethanolaminePSphosphatidylserinePPARperoxisome proliferator-activated factorTAGtriacylglycerol. activates long chain fatty acid (FA) to acyl-CoA, thereby enhancing vectorial FA transport across the plasma membrane (1Mashek D.G. Coleman R.A. Curr. Opin. Lipidol. 2006; 17: 274-278Crossref PubMed Scopus (115) Google Scholar) and providing substrates for most downstream pathways that metabolize FA. ACSL1 is one of five ACSL isoforms, each encoded by a separate gene. Its mRNA expression is highest in adipose tissue, liver, and heart (2Mashek D.G. Li L.O. Coleman R.A. J. Lipid Res. 2006; 47: 2004-2010Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar); and because Acsl1 mRNA and total ACSL1 activity increase 160-fold (3Marszalek J.R. Kitidis C. Dararutana A. Lodish H.F. J. Biol. Chem. 2004; 279: 23882-23891Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar) and 100-fold (4Coleman R.A. Reed B.C. Mackall J.C. Student A.K. Lane M.D. Bell R.M. J. Biol. Chem. 1978; 253: 7256-7261Abstract Full Text PDF PubMed Google Scholar), respectively, in differentiating 3T3-L1 adipocytes, ACSL1 has been thought to be important in activating FA destined for triacylglycerol (TAG) synthesis. In support of this idea, overexpressing ACSL1 in mouse heart increases cardiac myocyte TAG accumulation 12-fold and induces apoptotic pathways, cardiac hypertrophy, left ventricular dysfunction, and heart failure (5Chiu H.C. Kovacs A. Ford D.A. Hsu F.F. Garcia R. Herrero P. Saffitz J.E. Schaffer J.E. J. Clin. Invest. 2001; 107: 813-822Crossref PubMed Scopus (606) Google Scholar). However, Acsl1 mRNA expression is up-regulated in liver and adipose tissue by activators of peroxisome proliferator-activated factor α (PPARα) (6Schoonjans K. Staels B. Grimaldi P. Auwerx J. Eur. J. Biochem. 1993; 216: 615-622Crossref PubMed Scopus (105) Google Scholar, 7Frederiksen K.S. Wulff E.M. Sauerberg P. Mogensen J.P. Jeppesen L. Fleckner J. J. Lipid Res. 2004; 45: 592-601Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) via a PPAR response element in the promoter region of Acsl1 (8Schoonjans K. Watanabe M. Suzuki H. Mahfoudi A. Krey G. Wahli W. Grimaldi P. Staels B. Yamamoto T. Auwerx J. J. Biol. Chem. 1995; 270: 19269-19276Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar), suggesting a possible function related to the β-oxidation of fatty acids. Moreover, overexpression of ACSL1 in rat primary hepatocytes increases oleate incorporation into diacylglycerol (DAG) but does not increase TAG mass (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Thus, the exact role of ACSL1 in providing acyl-CoA for lipogenesis versus β-oxidation has remained uncertain. long chain acyl-CoA synthetase acylglycerol-3-phosphate acyltransferase analysis of variance acid-soluble metabolite cholesteryl ester diacylglycerol fatty acid fatty acid transport protein glycerol-3-phosphate acyltransferase insulin tolerance test lysophosphatidic acid lysophosphatidylcholine neomycin oral glucose tolerance test phosphatidylcholine phosphatidylethanolamine phosphatidylserine peroxisome proliferator-activated factor triacylglycerol. long chain acyl-CoA synthetase acylglycerol-3-phosphate acyltransferase analysis of variance acid-soluble metabolite cholesteryl ester diacylglycerol fatty acid fatty acid transport protein glycerol-3-phosphate acyltransferase insulin tolerance test lysophosphatidic acid lysophosphatidylcholine neomycin oral glucose tolerance test phosphatidylcholine phosphatidylethanolamine phosphatidylserine peroxisome proliferator-activated factor triacylglycerol. It has been suggested that lipid intermediates, including FAs, long chain acyl-CoAs, DAG, ceramide, and phosphatidic acid, rather than TAG accumulation per se, might underlie the development of insulin resistance (10Savage D.B. Petersen K.F. Shulman G.I. Physiol. Rev. 2007; 87: 507-520Crossref PubMed Scopus (743) Google Scholar, 11Postic C. Girard J. J. Clin. Invest. 2008; 118: 829-838Crossref PubMed Scopus (878) Google Scholar, 12Wymann M.P. Schneiter R. Nat. Rev. Mol. Cell Biol. 2008; 9: 162-176Crossref PubMed Scopus (921) Google Scholar, 13Shulman G.I. J. Clin. Invest. 2000; 106: PubMed Scopus Google Scholar). long chain glucose by and J. Biochem. J. PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar); and or be for factor a factor that of and glucose R. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Further, activates protein isoforms that insulin substrates and and thereby insulin (10Savage D.B. Petersen K.F. Shulman G.I. Physiol. Rev. 2007; 87: 507-520Crossref PubMed Scopus (743) Google Scholar). However, of not with in insulin K. Coleman R.A. Shulman G.I. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). Although acyl-CoA content in has been with diminished insulin P. J. Physiol. 2008; PubMed Scopus Google Scholar), in liver the and insulin is is and FA into the liver from is hepatic insulin resistance is with hepatic content of TAG and acyl-CoA C. M. W. Shulman G.I. 2001; PubMed Scopus Google Scholar). However, is in liver, the mice hepatic and insulin hepatic steatosis and acyl-CoA content M. M.P. J.R. Newgard C.B. Cell 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). the absence of glycerol-3-phosphate acyltransferase to against hepatic insulin resistance a increase in hepatic acyl-CoA against the of long chain in insulin resistance K. Coleman R.A. Shulman G.I. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). Although a content of might to insulin resistance in is not against insulin resistance might be by hepatic acyl-CoA content. the function of ACSL1 in liver, we constructed a mouse model with a liver-specific knock-out of ACSL1 Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25–35% decrease in long chain acyl-CoA content. model has to ACSL1 liver from hepatic steatosis and the incorporation of into and to a decrease in long chain acyl-CoA content is to protect the liver from high fat diet-induced insulin resistance. ACSL1 knock-out mice were by Rev. 2004; Google Scholar). was to a Acsl1 and was constructed in a neomycin and for and of was in length and was from whereas the was in length and from a of and a of the a was was into and the were in with and were by across the and of to and the of was from the via expression of were into from mouse to high were that the was to and with and and and for the were and to mice were with rat mice in liver C. 2000; PubMed Scopus Google Scholar). mice one and ACSL1 were to Acsl1L−/− mice five of or absence of the was by and and for and the knock-out of in Acsl1L−/− total was from Acsl1L−/− mice and and was by was with and of the region and a of in mice and a of in Acsl1L−/− mice of of the that in Acsl1L−/− was by that the product in Acsl1L−/− mice was to the absence of a and a (TAG) after a of acids in the Acsl1L−/− mice with a acid protein in the mice not mice were fed a and after either a or a was from the and adipose were in and high fat Acsl1L−/− and mice were fed a high fat from fat from and or from fat and from and for were was by mice were and were in and for and lipid content. hepatocytes were from fed and Acsl1L−/− by in liver a of the J. Cell Biol. PubMed Scopus Google Scholar). the were with a and with were after low and (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). hepatocytes were with of of for and for lipid J. Biochem. Physiol. PubMed Scopus Google Scholar) and acid-soluble metabolites a of FA (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Lipid were by in acid were and with a glucose tolerance and insulin tolerance were in mice of high fat or were for after the of the and with glucose for or with insulin for glucose was and and after the glucose or insulin with a R. T. A. PubMed Scopus Google Scholar). In mice that been fed a high fat for the were K. Coleman R.A. Shulman G.I. Cell Full Text Full Text PDF PubMed Scopus Google Scholar) with a to of glucose by a insulin to insulin a was mice were and with of or was via the the left liver was in tissue was and in a and and and were for and were used for with against ACSL1 expression was in liver, adipose tissue, and heart a from Cell from liver and heart or total from adipose tissue was by of was in the liver after of insulin the and were from Cell was used for of total ACSL activity in liver were with of liver in the of acid in and in a total of (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). activity was with of liver in a and R.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). activity was by the of acid to acid in a of and A.K. A. Biochem. 2006; PubMed Scopus Google Scholar). was by of liver total by for were by a Shulman G.I. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar), and liver TAG and total mass were hepatic lipid metabolite liver was with in K. Coleman R.A. Shulman G.I. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). and lipid metabolite were by high and individual and total lipid were by mass K. Coleman R.A. Shulman G.I. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). was and with for C. H. J. M. A. C.B. A. J.C. Mol. Cell Biol. 2001; PubMed Scopus Google Scholar). was the acylcarnitine mice fed a were were of liver were in and and acylcarnitine were by mass J. M. Shulman G.I. R. Newgard C.B. Nat. 2004; PubMed Scopus Google Scholar). plasma and after was from the or the total and insulin were with Coleman R.A. Mol. Cell Biol. PubMed Scopus Google Scholar). liver was isolated the and of total was to the high was with the in and the from of total were the for of are in in expression of the was to the and was to the the 2001; PubMed Scopus Google Scholar). are expressed and ACSL1 knock-out mice were of and were a analysis of variance with was of Acsl1 and was Acsl1L−/− mice were by the Acsl1L−/− were with the to Acsl1L−/− mice and were the that the of the and the not mice were used because that the the of ACSL1 expression or not Acsl1 mRNA was in Acsl1L−/− liver, the ACSL1 was observed for the mRNA from the other major ACSL isoforms in liver, and increase in the mRNA of the ACSL was not mRNA for fatty acid transport and have long chain acyl-CoA synthetase remained unchanged in Acsl1L−/− liver. a against ACSL1, we a in liver from liver, but not in liver from Acsl1L−/− whereas the was in adipose tissue and heart from and knock-out that the of ACSL1 was to liver with the and total ACSL activity in liver was and than in and decrease in ACSL activity that ACSL1 50% of total ACSL activity in liver and that other ACSL isoforms not for the ACSL activity activity from other ACSL and isoforms in liver. Acsl1L−/− mice from mice for or plasma metabolites Because has been that ACSL1 is up-regulated by a factor that increases FA β-oxidation (6Schoonjans K. Staels B. Grimaldi P. Auwerx J. Eur. J. Biochem. 1993; 216: 615-622Crossref PubMed Scopus (105) Google Scholar, 7Frederiksen K.S. Wulff E.M. Sauerberg P. Mogensen J.P. Jeppesen L. Fleckner J. J. Lipid Res. 2004; 45: 592-601Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar), we Acsl1L−/− and mice after a a knock-out and mice of and in total and hepatic was observed the mice were to and not suggesting that ACSL1 in liver not glucose ACSL isoforms acyl-CoAs, not for lipid but for lipid intermediates that are important for have suggested that and might insulin in and liver (10Savage D.B. Petersen K.F. Shulman G.I. Physiol. Rev. 2007; 87: 507-520Crossref PubMed Scopus (743) Google Scholar). the of a of ACSL1 in liver, the and of the lipid intermediates, acyl-CoAs, and were in mice fed low and high fat high fat from might be with a decrease in hepatic ACSL activity in Acsl1L−/− the and major of acyl-CoA were In the high fat the total and major and fed either the or the high fat the content of acyl-CoA in knock-out mice liver was and respectively, than in liver from mice major acyl-CoA in liver, was and in knock-out mice fed the or the high fat decreases in acyl-CoA are consistent with the of ACSL1 H. T. H. Suzuki H. Yamamoto T. Eur. J. Biochem. PubMed Scopus Google lipid metabolites from Acsl1L−/− and mice fed a high fat or a for liver lipid fat fat with mice fed the same with fat in the same with mice fed the same with fat in the same acid with mice with mice fed the same with fat in the same with mice in a the content of acyl-CoA, liver from Acsl1L−/− mice fed the high fat total and than liver and and were to and the mRNA and activity of the that and acyl-CoA to form the isoforms, of the in mRNA was the increase in total activity was not of protein in versus of protein in knock-out Because the increase in might have been by a decrease in we the activity of to form phosphatidic was and knock-out mice not Thus, the increase in in Acsl1L−/− liver from high fat mice hepatic content in mice fed the was in the decrease in total acyl-CoA content not the hepatic content of in Acsl1L−/− liver, was for mice were fed either the or the high fat and Acsl1L−/− was to that of for and and respectively, mice were fed the and and and respectively, mice were fed the high fat tissue and to we that each ACSL isoform destined for downstream pathways R.A. J. PubMed Scopus Google Scholar). the liver content of hepatocytes from and Acsl1L−/− mice were with the incorporation of the fatty acid into TAG was in the knock-out the product of FA was in the knock-out In addition, [14C]oleate into isolated Acsl1L−/− hepatocytes a was to that of not Further, Acsl1L−/− and mice plasma after were for or fed with the high fat However, a analysis of the liver acylcarnitine by mass that Acsl1L−/− liver and and respectively, and chain are mitochondrial intermediates that are from and the of FA mitochondrial FA J. M. Shulman G.I. R. Newgard C.B. Nat. 2004; PubMed Scopus Google Scholar). decreases in long chain were consistent with the incorporation of from [14C]oleate into and suggested that long chain FA in liver is by ACSL1 increase in in suggested that FA and the mRNA for acyl-CoA a in was in Acsl1L−/− liver. Because in with ACSL1 of a of and fatty acids with in FA H. J. T. K. T. Yamamoto T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. Suzuki H. H. Yamamoto T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the lipid in Acsl1L−/− liver was to a be expressed in fed the high fat TAG in and Acsl1L−/− liver DAG, and lysophosphatidylcholine In Acsl1L−/− liver, small but were observed in the of in Acsl1L−/− liver and a percentage of and and a percentage of with mice with in liver, Acsl1L−/− liver and and and were observed in the for FA of in Acsl1L−/− liver were after the mice were fed a high fat for suggesting that ACSL1 a of to either or FA of from Acsl1L−/− and and from of mice fed a high fat or a for were and from five versus mice fed the same versus fat in the same the in the hepatic content of including and not in Acsl1L−/− liver fat the of and in TAG in and knock-out but was Acsl1L−/− liver a percentage of and in TAG and to have percentage of TAG fed the high fat that a 50% decrease in total activity a of ACSL1 the TAG Because the Acsl1L−/− liver 25–35% acyl-CoA than we Acsl1L−/− mice be protected from developing hepatic and insulin resistance. and were in mice fed a high fat for with mice fed the mice fed the high fat glucose and a the the and but were observed in either the or the and the that long might a we the tissue and insulin in mice after were fed a high fat for ACSL1 hepatic and insulin hepatic glucose or glucose Thus, a hepatic ACSL1 not protect the mice from diet-induced or hepatic insulin resistance. Further, insulin into the in and knock-out mice consistent with the that the 25–35% hepatic acyl-CoA content observed in the knock-out liver not hepatic insulin chain isoforms of and and for lipid lipid and lipid the of the ACSL ACSL1, in H. J. T. K. T. Yamamoto T. J. Biol. Chem. Full Text PDF PubMed Google Scholar), ACSL isoforms have been each with D.G. Coleman R.A. J. D.A. P. W. A. Schaffer J.E. A. Yamamoto J. Lipid Res. 2004; 45: Full Text Full Text PDF PubMed Scopus Google Scholar). has been in our of ACSL primary tissue and However, because for individual ACSL isoforms have been the exact role of each ACSL in lipid and lipid remained that ACSL isoforms for pathways and that individual ACSL isoforms might have in overexpression of ACSL1 and (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, D.G. Coleman R.A. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). ACSL1 in primary hepatocytes increases the incorporation of oleate into and and decreases incorporation into but has In overexpressing in FA TAG and but not or synthesis. However, are with possible protein be or the product the of downstream Thus, we constructed a mouse in ACSL1 in liver to the role of ACSL1 in hepatic the we the Acsl1L−/− in liver, by the absence of the the of Acsl1L−/− mRNA by and the absence of ACSL1 activity of ACSL in liver was 50% than in that ACSL1 is a major hepatic ACSL in mRNA from the other major ACSL and isoforms were not and the of ACSL activity suggested that a increase of other with ACSL activity not the of ACSL1 and 50% of ACSL activity in liver not have a major mouse or and adipose were of and the plasma of total and not of ACSL to into that are the that with ACSL activity might FA (1Mashek D.G. Coleman R.A. Curr. Opin. Lipidol. 2006; 17: 274-278Crossref PubMed Scopus (115) Google Scholar). In ACSL1 was in to that increase the of long chain into J.E. Lodish H.F. Full Text PDF PubMed Scopus Google Scholar). However, in rat primary ACSL1 not increase total FA (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), either because ACSL1 does not FA in hepatocytes or because this model not increase high of FA In the the 25–35% total acyl-CoA and major acyl-CoA in the Acsl1L−/− liver be to the decrease in ACSL activity or to the of ACSL activity and FA against the is the that plasma FA were in and Acsl1L−/− mice and the that FA was in and Acsl1L−/− Further, FA content was unchanged or in Acsl1L−/− liver. major in the liver-specific Acsl1L−/− mice were the in FA and the decreases in TAG and by isolated observed increases in and and decreases in and in in in Thus, the FA preferences of ACSL1 T. Suzuki H. H. Yamamoto T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) not the in FA observed in liver a that and Further, one not have that FA in and but not in and that have FA to TAG the function of ACSL1 in liver has been the one hepatic Acsl1 mRNA is in and with fatty K. T. T. K. Suzuki H. Yamamoto T. PubMed Scopus Google Scholar, H. T. M. K. K. T. K. K. J.R. PubMed Scopus Google Scholar), suggesting a with TAG synthesis. However, that for FA β-oxidation hepatic Acsl1 mRNA (6Schoonjans K. Staels B. Grimaldi P. Auwerx J. Eur. J. Biochem. 1993; 216: 615-622Crossref PubMed Scopus (105) Google Scholar, 7Frederiksen K.S. Wulff E.M. Sauerberg P. Mogensen J.P. Jeppesen L. Fleckner J. J. Lipid Res. 2004; 45: 592-601Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) via a PPAR response element in the promoter (8Schoonjans K. Watanabe M. Suzuki H. Mahfoudi A. Krey G. Wahli W. Grimaldi P. Staels B. Yamamoto T. Auwerx J. J. Biol. Chem. 1995; 270: 19269-19276Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). Moreover, ACSL1 is in liver D.A. J.E. Coleman R.A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) and in J. Biochem. 2006; PubMed Scopus Google Scholar), the for TAG and FA ACSL1 in mouse or mouse liver TAG (5Chiu H.C. Kovacs A. Ford D.A. Hsu F.F. Garcia R. Herrero P. Saffitz J.E. Schaffer J.E. J. Clin. Invest. 2001; 107: 813-822Crossref PubMed Scopus (606) Google Scholar, L. P. Yamamoto Schaffer J.E. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. L. L. J. Physiol. 2006; PubMed Scopus Google Scholar), but overexpression in rat primary hepatocytes not oleate incorporation into TAG (9Li L.O. Mashek D.G. An J. Doughman S.D. Newgard C.B. Coleman R.A. J. Biol. Chem. 2006; 281: 37246-37255Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), and of Acsl1 in not oleate incorporation into TAG H. J. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). In the the ACSL1 not protect mice from diet-induced hepatic in isolated [14C]oleate incorporation into TAG was diminished by Although our that ACSL1 is not for hepatic TAG is possible that Acsl1L−/− liver to the ACSL1 by the of that are in the of the of in plasma after for or after low or high fat diets, a in β-oxidation is by Acsl1 mRNA in liver is up-regulated by a major factor that increases the expression of in FA the but decrease in incorporation of [14C]oleate into in isolated the decreases in liver are consistent with a of into the of mitochondrial β-oxidation J. M. Shulman G.I. R. Newgard C.B. Nat. 2004; PubMed Scopus Google Scholar), and the increase in and the increase in acyl-CoA mRNA a increase of FA in a our that TAG and β-oxidation of long chain FA are in Acsl1L−/− liver. In the of TAG in tissues, increases in acyl-CoA, DAG, and have each been to insulin resistance (10Savage D.B. Petersen K.F. Shulman G.I. Physiol. Rev. 2007; 87: 507-520Crossref PubMed Scopus (743) Google Scholar, 11Postic C. Girard J. J. Clin. Invest. 2008; 118: 829-838Crossref PubMed Scopus (878) Google Scholar, 12Wymann M.P. Schneiter R. Nat. Rev. Mol. Cell Biol. 2008; 9: 162-176Crossref PubMed Scopus (921) Google Scholar). In Acsl1L−/− mice fed a high fat hepatic total acyl-CoA content and major acyl-CoA were than in and we the mice be protected from developing insulin resistance. ACSL1 increase in hepatic content and a decrease in but not the total of in lipid intermediates, Acsl1L−/− mice were in glucose in glucose and insulin and in the of insulin to with a fat for Acsl1L−/− mice and Further, a study the in hepatic or insulin in mice fed a high fat for study that increase in hepatic acyl-CoA content does not in insulin resistance K. Coleman R.A. Shulman G.I. Cell Full Text Full Text PDF PubMed Scopus Google Scholar); our study suggests that a decrease in acyl-CoA content does not protect against insulin resistance liver TAG content is In this is the knock-out model to study the role of ACSL1 in liver and in the absence of hepatic ACSL1, a 50% decrease in ACSL and a 25–35% decrease in acyl-CoA were observed in liver or or plasma lipid and Acsl1L−/− mice were not protected from diet-induced hepatic but consistent were in the FA of the major and TAG and β-oxidation were with