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Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2

Erez F. Scapa^*, Alessandro Pocai^,1, Michele K. Wu^*, Roger Gutierrez-Juarez, Lauren Glenz^*, Keishi Kanno^*, Hua Li, Sudha Biddinger, Linda A. Jelicks, Luciano Rossetti^,1 and David E. Cohen^*,||,2

^* Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;

Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, and

Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York, USA;

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA; and

^|| Division of Health and Sciences and Technology, Harvard-Massachusetts Institute of Technology, Boston, Massachusetts, USA

²Correspondence: Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. E-mail: dcohen{at}partners.org

Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is a highly specific intracellular lipid binding protein with accentuated expression in oxidative tissues. Here we show that decreased plasma concentrations of glucose and free fatty acids in fasting PC-TP-deficient (Pctp^–/–) mice are attributable to increased hepatic insulin sensitivity. In hyperinsulinemic-euglycemic clamp studies, Pctp^–/– mice exhibited profound reductions in hepatic glucose production, gluconeogenesis, glycogenolysis, and glucose cycling. These changes were explained in part by the lack of PC-TP expression in liver per se and in part by marked alterations in body fat composition. Reduced respiratory quotients in Pctp^–/– mice were indicative of preferential fatty acid utilization for energy production in oxidative tissues. In the setting of decreased hepatic fatty acid synthesis, increased clearance rates of dietary triglycerides and increased hepatic triglyceride production rates reflected higher turnover in Pctp^–/– mice. Collectively, these data support a key biological role for PC-TP in the regulation of energy substrate utilization.—Scapa, E. F., Pocai, A., Wu, M. K., Gutierrez-Juarez, R., Glenz, L., Kanno, K., Li, H., Biddinger, S., Jelicks, L. A., Rossetti, L., Cohen, D. E. Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2.

Key Words: fatty acid • triglyceride • glucose • respiratory quotient • phospholipid