Regulation of fatty acid trafficking in liver by thioesterase superfamily member 1

Thioesterase superfamily member 1 (Them1) is an acyl-CoA thioesterase that is highly expressed in brown adipose tissue, where it functions to suppress energy expenditure. Lower Them1 expression levels in the liver are upregulated in response to high-fat feeding. Them1−/− mice are resistant to diet-induced obesity, hepatic steatosis, and glucose intolerance, but the contribution of Them1 in liver is unclear. To examine its liver-specific functions, we created conditional transgenic mice, which, when bred to Them1−/− mice and activated, expressed Them1 exclusively in the liver. Mice with liver-specific Them1 expression exhibited no changes in energy expenditure. Rates of fatty acid oxidation were increased, whereas hepatic VLDL triglyceride secretion rates were decreased by hepatic Them1 expression. When fed a high-fat diet, Them1 expression in liver promoted excess steatosis in the setting of reduced rates of fatty acid oxidation and preserved glycerolipid synthesis. Liver-specific Them1 expression did not influence glucose tolerance or insulin sensitivity, but did promote hepatic gluconeogenesis in high-fat-fed animals. This was attributable to the generation of excess fatty acids, which activated PPARα and promoted expression of gluconeogenic genes. These findings reveal a regulatory role for Them1 in hepatocellular fatty acid trafficking. Thioesterase superfamily member 1 (Them1) is an acyl-CoA thioesterase that is highly expressed in brown adipose tissue, where it functions to suppress energy expenditure. Lower Them1 expression levels in the liver are upregulated in response to high-fat feeding. Them1−/− mice are resistant to diet-induced obesity, hepatic steatosis, and glucose intolerance, but the contribution of Them1 in liver is unclear. To examine its liver-specific functions, we created conditional transgenic mice, which, when bred to Them1−/− mice and activated, expressed Them1 exclusively in the liver. Mice with liver-specific Them1 expression exhibited no changes in energy expenditure. Rates of fatty acid oxidation were increased, whereas hepatic VLDL triglyceride secretion rates were decreased by hepatic Them1 expression. When fed a high-fat diet, Them1 expression in liver promoted excess steatosis in the setting of reduced rates of fatty acid oxidation and preserved glycerolipid synthesis. Liver-specific Them1 expression did not influence glucose tolerance or insulin sensitivity, but did promote hepatic gluconeogenesis in high-fat-fed animals. This was attributable to the generation of excess fatty acids, which activated PPARα and promoted expression of gluconeogenic genes. These findings reveal a regulatory role for Them1 in hepatocellular fatty acid trafficking. Upon uptake or synthesis within hepatocytes, long-chain FFAs are activated by long-chain acyl-CoA synthetases (ACSLs) to form fatty acyl-CoA molecules, which may then become incorporated into complex lipids or undergo oxidation within mitochondria or peroxisomes. This thioesterification reaction is reversed by acyl-CoA thioesterases (ACOTs) (1.Grevengoed T.J. Klett E.L. Coleman R.A. Acyl-CoA metabolism and partitioning.Annu. Rev. Nutr. 2014; 34: 1-30Crossref PubMed Scopus (226) Google Scholar, 2.Tillander V. Alexson S.E.H. Cohen D.E. Deactivating fatty acids: acyl-CoA thioesterase-mediated control of lipid metabolism.Trends Endocrinol. Metab. 2017; 28: 473-484Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), a family of enzymes with well-characterized biochemical activities, but with biological functions that remain largely unexplored (2.Tillander V. Alexson S.E.H. Cohen D.E. Deactivating fatty acids: acyl-CoA thioesterase-mediated control of lipid metabolism.Trends Endocrinol. Metab. 2017; 28: 473-484Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). Multiple ACSL and ACOT isoforms are expressed in cells, suggesting a role of these enzymes in the formation of distinct pools of fatty acids/acyl-CoAs to be channeled into specific metabolic pathways (1.Grevengoed T.J. Klett E.L. Coleman R.A. Acyl-CoA metabolism and partitioning.Annu. Rev. Nutr. 2014; 34: 1-30Crossref PubMed Scopus (226) Google Scholar). Thioesterase superfamily member 1 (Them1) [synonyms: brown fat inducible thioesterase (BFIT), steroidogenic acute regulatory protein-related lipid transfer (START) domain 14 (StarD14)/Acot11] is enriched in mouse brown adipose tissue (BAT), and its expression is markedly upregulated by cold ambient temperatures (3.Adams S.H. Chui C. Schilbach S.L. Yu X.X. Goddard A.D. Grimaldi J.C. Lee J. Dowd P. Colman S. Lewin D.A. BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity.Biochem. J. 2001; 360: 135-142Crossref PubMed Google Scholar, 4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). Genetic disruption of Them1 in mice resulted in increased energy expenditure, as well as resistance to diet-induced obesity and diabetes (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). Suppression of energy expenditure in BAT occurred when Them1 limited the flux of fatty acids from lipid droplets (LDs) to mitochondria for β-oxidation by inhibiting lipolysis of LD triglycerides (TGs) (5.Okada K. LeClair K.B. Zhang Y. Li Y. Ozdemir C. Krisko T.I. Hagen S.J. Betensky R.A. Banks A.S. Cohen D.E. Thioesterase superfamily member 1 cold by the oxidation of lipid fatty acids in brown adipose Metab. PubMed Scopus Google Scholar). of Them1−/− mice were for resistance to diet-induced insulin resistance and to hepatic steatosis (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). the of Them1 of Them1−/− mice exhibited and of in fatty acid of decreased expressed levels in the hepatic expression of Them1 is (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar, S. Cohen D.E. of thioesterase superfamily member thioesterase for metabolic 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). the of of Them1 (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar), but these were to Them1 expression in the liver or were to in energy expenditure unclear. role for Them1 in liver is by the that Them1 is upregulated in response to high-fat and of acyl-CoA PubMed Scopus Google Scholar). To its role in hepatic lipid we created a conditional Them1 transgenic which, when bred to a Them1−/− expression. these mice with transgenic mice to Them1 in the liver. in mice, hepatic Them1 promoted fatty acid and in response to high-fat Them1 promotes the of hepatic hepatic expression of Them1 did not influence energy expenditure, glucose or insulin expression did promote hepatic glucose in response to high-fat by PPARα to promote the expression of gluconeogenic genes. mice were by of was into the of the which of a and by mouse and by a was by This for the expression of Them1 in a to and the of mouse Them1 and for the of Them1 and of the was by and was then by and and into of from mice were for of were for of the by from the and Mice that were for the were then by to Mice with of the were for Them1 transgenic mice were with Them1−/− mice (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. 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M.W. for of PubMed Scopus Google Scholar). are as with was by when with to be or by when or To the biological functions of hepatic we created a conditional transgenic mouse with a which for expression. was bred to a Them1−/− and activated in liver by with an This created mice that Them1 exclusively in the liver and expression of transgenic Them1 in the of and high-fat-fed was by and of ACOT for the of no in were was a in of liver from mice with the against the that these changes by we changes in expression for of the were no in the fed or the high-fat exhibited of energy expenditure and a role for Them1 in hepatic fatty acid were but in of mice with mice were no mice increased hepatic and in to the and was reversed in mice were no changes in hepatic of or or When with of increased fatty acid oxidation in BAT from Them1−/− mice (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. 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PubMed Scopus Google Scholar), these findings to examine Them1 fatty acid oxidation within the liver. the metabolic of fatty acids for oxidation or complex lipid its to an acyl-CoA form by ACSL we Them1 ACSL were increased by in and was in mice were no in the expression levels of of the isoforms that levels or specific of were by When with was a in rates of fatty acid oxidation in of mice, which were liver-specific expression of Them1 in mice of a of hepatic fatty acid were decreased in by but was not by the of Them1 expression in mice These changes in fatty acid oxidation rates occurred in the of of Them1 expression levels of or its and fatty acid Them1 expression promotes fatty acid oxidation in of mice were ACSL expression of isoforms rates of oxidation of and expression of and its to changes in fatty acid of hepatic FFAs and may be by changes in fatty acid and rates of fatty acid uptake were from as well as the expression of that fatty acids uptake into of increased rates of were increased in the of Them1 expression and by liver-specific expression were no changes in levels of fatty acid or or of which are the fatty acid expressed Cohen D.E. metabolism in the Google Scholar). for in rates of fatty acid and synthesis. were no in the expression levels of the and and or in fatty acid and were no changes in the of which the in the synthesis of and R.A. Lee of synthesis and PubMed Scopus Google Scholar). of into the in the form of and VLDL which and mice exhibited in with the control mice exhibited a in a that was in expression in the with the for were increased in and mice by and the were no changes in mice is in the in with and the of Them1 that we (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). mice, was a in the rates of secretion in mice with its This was reversed when Them1 expression was in of mice did not secretion as of assessment of hepatic secretion in to it is that hepatic Them1 and the influence of Them1 expression the of hepatic steatosis in response to high-fat feeding. with the increased expression Them1 expression in the of mice was induced by high-fat high-fat-fed mice, to in mice, but were in mice an increased of in high-fat-fed mice were no changes in hepatic of to in Them1−/− mice a (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar), the of Them1 in mice did not hepatic with the Them1 expression in of mice increased in liver by was a in hepatic in mice whereas hepatic of and were were no changes in hepatic ACSL in high-fat-fed mice, whereas a was in the This occurred in the of changes in expression levels of Rates of fatty acid oxidation were increased in mice, and was in mice to increased of the of hepatic Them1 reversed expression levels of to by and in high-fat-fed and mice, with in the and in fatty oxidation rates to examine the influence of hepatic Them1 expression with from mice exhibited a in to of a response that was in from mice was a in in mice with that was in the mice To that the the β-oxidation of fatty acids, were with the was no response to and no in or that fatty acids were by β-oxidation against a in fatty acid were no changes in or expression of fatty acid in mouse were no changes in or were that of and which are of increased in of and in high-fat-fed mice exhibited an in with control and were in and of and in mice with and was reversed in the of and were decreased in the mice by and to and were by the transgenic expression of Them1 were to hepatic rates of secretion in high-fat-fed This may be by in that high-fat secretion rates by hepatic fatty acids from VLDL in of β-oxidation A.D. of a high-fat the of into hepatic J. Google Scholar, A.D. VLDL secretion of is by a high-fat J. Google Scholar). we Them1 expression in the liver glucose with glucose were increased by in mice and to remain in mice was a decreased insulin in mice was a in glucose of high-fat-fed mice insulin to by in mice and by in high-fat-fed mice with mice were no changes in was in the gluconeogenic and in high-fat-fed mice glucose insulin tolerance or high-fat by mice to increased rates of hepatic glucose and was reversed by Them1 expression in the liver with the of gluconeogenic were increased for mice This was to the specific functions of Them1 in liver and the to which these to the in Them1−/− mice (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar, K. LeClair K.B. Zhang Y. Li Y. Ozdemir C. Krisko T.I. Hagen S.J. Betensky R.A. Banks A.S. Cohen D.E. Thioesterase superfamily member 1 cold by the oxidation of lipid fatty acids in brown adipose Metab. PubMed Scopus Google Scholar), the metabolic exhibited in high-fat-fed (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). was that Them1 a regulatory role in the hepatocellular of fatty acids it to to hepatic steatosis in high-fat-fed mice, Them1 in liver did not influence energy expenditure, did it a glucose or insulin mouse we for hepatic Them1 to and where the of Them1 into of mice reversed the of the mouse to the the of the into the metabolic functions of where unique were in the setting of liver-specific the were to the levels of we the expression of that by the of the of mice Them1 for mice did not Them1−/− mice in (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). was a of and an of increased energy expenditure of high-fat-fed mice when with conditional transgenic These were attributable to the distinct of mice in the with the mice we Them1−/− mice in the were a and mice were in in (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar), Them1−/− mice and were and a and these in to diet-induced obesity (3.Adams S.H. Chui C. Schilbach S.L. Yu X.X. Goddard A.D. Grimaldi J.C. Lee J. Dowd P. Colman S. Lewin D.A. BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity.Biochem. J. 2001; 360: 135-142Crossref PubMed Google Scholar, A. J. J. J. of mouse high-fat diet-induced Metab. PubMed Scopus Google Scholar, C. J. for diet-induced obesity in a J. Nutr. 2017; PubMed Scopus Google Scholar). changes in to be to the mouse to Them1 expression in the liver. mice into the metabolic role for Them1 in hepatic fatty acid from a role for the in FFAs that become for (2.Tillander V. Alexson S.E.H. Cohen D.E. Deactivating fatty acids: acyl-CoA thioesterase-mediated control of lipid metabolism.Trends Endocrinol. Metab. 2017; 28: 473-484Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Y. Li Y. S. Cohen D.E. Thioesterase superfamily member and transfer to promote fatty acid oxidation and control glucose 2014; 34: PubMed Scopus Google Scholar). are into mitochondria thioesterification by which with the fatty acyl-CoA in the (1.Grevengoed T.J. Klett E.L. Coleman R.A. Acyl-CoA metabolism and partitioning.Annu. Rev. Nutr. 2014; 34: 1-30Crossref PubMed Scopus (226) Google Scholar, K. J. is of an fatty acid transfer Full Text Full Text PDF PubMed Scopus Google incorporated into by that of (1.Grevengoed T.J. Klett E.L. Coleman R.A. Acyl-CoA metabolism and partitioning.Annu. Rev. Nutr. 2014; 34: 1-30Crossref PubMed Scopus (226) Google Scholar). findings that Them1 may the of Them1 is not with that Them1 in liver is largely (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). This an to for the of to the of for increased fatty acid the in in mice with that Them1 that the promotes of to the mitochondria for the of fatty acid oxidation rates and hepatic secretion rates Them1 promotes the oxidation of a fatty acid that be for into VLDL the expression levels of Them1 in the liver are (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar), are upregulated by high-fat and of acyl-CoA PubMed Scopus Google Scholar), which rates of fatty acid oxidation of fat liver and PubMed Scopus Google Scholar). the fatty acid oxidation rates were reduced by hepatic Them1 expression in high-fat-fed mice and in with of a role from Them1 in fatty acid the increased oxidation rates in were by inhibiting excess FFAs were in the setting of Them1 expression did not these Them1 promoted the of fatty acids as in as by an hepatic steatosis in hepatic were reduced by Them1 expression in high-fat-fed mice, did not to be the of excess the by which Them1 hepatic steatosis was by lipolysis of LD as we in mouse brown in which excess by Them1 adipose of fatty which to suppress the of adipose (5.Okada K. LeClair K.B. Zhang Y. Li Y. Ozdemir C. Krisko T.I. Hagen S.J. Betensky R.A. Banks A.S. Cohen D.E. Thioesterase superfamily member 1 cold by the oxidation of lipid fatty acids in brown adipose Metab. PubMed Scopus Google Scholar). This is by an in ACSL in of high-fat-fed potential that occurred in hepatic secretion in response to rates of reduced fatty acid oxidation was to for the increased in of high-fat-fed mice with Them1 we in expression of and its and S. S. Sci. PubMed Scopus Google Scholar, S. and of Metab. 2014; PubMed Scopus Google Scholar). This the generation of excess fatty acids, which was by in hepatic These changes in gene expression did not to metabolic rates of fatty acid oxidation were the that was hepatic expression of Them1 was to influence glucose which was in Them1−/− mice to (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). did not that hepatic Them1 expression to insulin Mice Them1 exhibited increased insulin when fed or high-fat as by for and with reduced of glucose we that the expression of Them1 no glucose (4.Zhang Y. Li Y. Niepel M.W. Kawano Y. Han S. Liu S. Marsili A. Larsen P.R. Lee C.H. Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.Proc. Natl. Acad. Sci. USA. 2012; 109: 5417-5422Crossref PubMed Scopus (69) Google Scholar). in for in high-fat-fed mice, with increased gluconeogenic gene expression and S. and of Metab. 2014; PubMed Scopus Google Scholar). the findings a role for Them1 in hepatocellular of but not in the of energy expenditure or of glucose metabolic Them1 functions to β-oxidation and from VLDL the setting of high-fat Them1 promotes hepatic by LD fatty liver is by excess hepatic and is the of liver Y. of fatty liver assessment of and PubMed Scopus Google Scholar), with that remain limited K. and of fatty liver from the for the of of 2017; Google Scholar). that of hepatic Them1 expression in the setting of to hepatic steatosis, the of its may be in the of with acyl-CoA thioesterase acyl-CoA long-chain the brown adipose tissue fatty acid 1 fatty acid glucose tolerance insulin tolerance mice lipid tolerance thioesterase superfamily member 1 triglyceride