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

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

Abstract

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fatty Acids / metabolism*
  • Female
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Palmitoyl-CoA Hydrolase / deficiency
  • Palmitoyl-CoA Hydrolase / genetics
  • Palmitoyl-CoA Hydrolase / metabolism*

Substances

  • Fatty Acids
  • Thea protein, mouse
  • Palmitoyl-CoA Hydrolase