Thioesterase Superfamily Member 2 (Them2) Promotes the Hepatic Oxidation of Plasma Free Fatty Acids

Abstract

Them2 is a mitochondria‐associated long chain acyl‐CoA thioesterase that hydrolyzes fatty acyl‐CoAs to free fatty acids and CoA in vitro. However, the metabolic role of Them2 in liver remains unclear. Here we utilized chow and high fat fed Them2+/+ and Them2−/− mice to explore regulation of hepatic lipid metabolism by Them2. The absence of Them2 expression reduced total and mitochondrial fatty acyl‐CoA thioesterase activities in liver. This led to a 28% increase in fatty acyl‐CoA concentrations, which was mainly attributable to increases in C16:0, C18:0 and C18:3‐fatty acyl CoA molecular species. Reduced hepatic FGF21 mRNA levels along with decreased plasma β‐hydroxybutyrate concentrations implied that fatty acid oxidation was reduced in livers of Them2−/− mice. Whereas high fat fed Them2+/+ mice developed hepatic steatosis, livers of Them2−/− mice did not accumulate excess triglycerides. In the absence of changes in lipogenic gene expression, this was attributable to increases in hepatic triglyceride secretion rates and decreases in free fatty acid uptake into the liver, as reflected by lower CD36 mRNA levels. Collectively, these findings suggest that the fatty acyl‐CoA thioesterase activity of Them2 in liver promotes oxidation of plasma free fatty acids and reduces their hepatic secretion as triglycerides. Supported by the NIH and AHA.