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J Lipid Res. 2018 Feb;59(2):368-379. doi: 10.1194/jlr.M081455. Epub 2017 Dec 5.

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

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Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10021.
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10021


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.


fatty acid/metabolism; fatty acid/oxidation; fatty acyl-CoA; lipids; nonalcoholic fatty liver disease; obesity; triglycerides; very low density lipoprotein

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