Thioesterase Superfamily Member 2 (Them2) and Phosphatidylcholine Transfer Protein (PC-TP) Interact To Promote Fatty Acid Oxidation and Control Glucose Utilization

Abstract

Thioesterase superfamily member 2 (Them2) is a mitochondrion-associated long-chain fatty acyl coenzyme A (CoA) thioesterase that is highly expressed in the liver and oxidative tissues. Them2 activity in vitro is increased when it interacts with phosphatidylcholine transfer protein (PC-TP), a cytosolic lipid binding protein. Them2^−/− and Pctp^−/− mice exhibit enhanced hepatic insulin sensitivity and increased adaptive thermogenesis, and Them2^−/− mice are also resistant to diet-induced hepatic steatosis. Although we showed previously that a Them2–PC-TP complex suppresses insulin signaling, the enzymatic activity of Them2 suggests additional direct involvement in regulating hepatic nutrient homeostasis. Here we used cultured primary hepatocytes to elucidate biochemical and cellular mechanisms by which Them2 and PC-TP regulate lipid and glucose metabolism. Under conditions simulating fasting, Them2^−/− and Pctp^−/− hepatocytes each exhibited decreased rates of fatty acid oxidation and gluconeogenesis. In results indicative of Them2-dependent regulation by PC-TP, chemical inhibition of PC-TP failed to reproduce these changes in Them2^−/− hepatocytes. In contrast, rates of glucose oxidation and lipogenesis in the presence of high glucose concentrations were decreased only in Them2^−/− hepatocytes. These findings reveal a primary role for Them2 in promoting mitochondrial oxidation of fatty acids and glucose in the liver.

ACKNOWLEDGMENTS

The work was supported by National Institutes of Health grants R37 DK48873 and R01 DK56626 to D.E.C. and the Harvard Digestive Diseases Center (P30 DK034854). Y.K. was funded in part by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Global COE Program Global Center of Excellence for Education and Research on Signal Transduction Medicine in the Coming Generation). B.A.E. was funded in part by a Liver Scholar Award from the American Association for the Study of Liver Diseases.