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

• Main Authors: Anal Desai, Michele Alves-Bezerra, Yingxia Li, Cafer Ozdemir, Curtis J. Bare, Yue Li, Susan J. Hagen, David E. Cohen
• Format: Article
• Language: English
• Published: Elsevier 2018-02-01
• Series: Journal of Lipid Research
• Subjects: lipids; nonalcoholic fatty liver disease; obesity; triglycerides; fatty acid/metabolism; fatty acid/oxidation
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520342395

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.