Thioesterase Superfamly Member 2 (Them2): Metabolic Control of Hepatic Fatty Acid Channeling and Pathogenic Role in Non‐Alcoholic Fatty Liver Disease
Authors: Cohen David E 
Published: November 2023

Thioesterase superfamily member 2 (Them2; synonym acyl‐CoA thioesterase 13) is a long chain fatty acyl‐CoA thioesterase that is associated with mitochondria and enriched in liver. We identified Them2 as an interacting protein of phosphatidylcholine transfer protein (PC‐TP), a cytosolic lipid binding protein. Pctp−/− mice exhibit altered fatty acid metabolism that is accompanied by reduced hepatic glucose production. Although we previously showed that a Them2‐PC‐TP complex suppresses insulin signaling, the increased enzymatic activity of Them2 upon binding PC‐TP in vitro suggests direct involvement in hepatic fatty acid trafficking. To test this possibility, we generated mice lacking Them2. In livers of Them2−/− mice compared with Them2+/+ controls, reduced mitochondrial thioesterase activities were accompanied by increased fatty acyl‐CoA concentrations and a reciprocal decrease in free fatty acid concentrations. When fed a high‐fat diet, Them2−/− mice were resistant to increases in hepatic glucose production and steatosis. Under simulated conditions of fasting, cultured primary Them2−/− hepatocytes exhibited decreased fatty acid oxidation rates, as well as decreased rates of gluconeogenesis from lactate and pyruvate. These findings reveal a functional role for Them2 in promoting mitochondrial oxidation of fatty acids within the liver, which under fasting conditions facilitates gluconeogenesis by increasing TCA cycle activity. Them2 promotes fatty acid oxidation apparently by generating free fatty acids that are re‐esterified to CoA by long chain acyl‐CoA synthetase 1 (ACSL1) to enable mitochondrial uptake by carnitine palmitoyl transferase 1 (CPT1). Under fed conditions, ACSL1‐generated fatty acyl‐CoAs may instead become substrates for GPAT1, which initiates the synthesis of glycerolipids. Diacylglycerols and phosphatidic acid suppress insulin signaling by activating PKCɛ or inactivating mTORC2, respectively, and GPAT1 overexpression in liver promotes hepatic insulin resistance. Because livers of high fat fed Them2−/− mice exhibit increased sensitivity to insulin compared to controls, we further examined whether Them2 promotes GPAT1‐mediated suppression of insulin signaling. Using recombinant adenovirus, GPAT1 or GFP was overexpressed in mouse livers. GPAT1 but not GFP overexpression promoted hepatic synthesis of glycerolipids in both Them2+/+ and Them2−/− mice. As evidenced by increased ratios of membrane/cytosolic PKCɛ, GPAT1 overexpression activated PKCɛ in livers of Them2+/+ mice, an effect that was attenuated in the absence of Them2 expression. Consistent with the contribution of Them2 to GPAT1‐induced hepatic insulin resistance, when primary mouse hepatocytes were infected with GPAT1 adenovirus, insulin‐mediated Akt phosphorylation was increased at S473 and T308 in the absence of Them2 expression. Taken together, these reveal that Them2 regulates metabolic channeling of fatty acids within the liver and contributes to the pathogenesis of non‐alcoholic fatty liver disease.

Support or Funding Information

Support: NIH DK48873 and DK56626