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

Abstract

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.

The mammalian START domain protein family in lipid transport in health and disease

“…Although the predicted phenotype(s) was not observed with the Pctp K/K mice, new data indicate STARD2/PCTP functions in insulin-regulated pathways to maintain glucose homeostasis (Scapa et al 2008, Shishova et al 2011. Fasting serum glucose and free fatty acid levels are significantly decreased in Pctp K/K mice compared with wild-type counterparts due to increased insulin sensitivity (Scapa et al 2008). In addition, hepatic SREBP1c expression is decreased in Pctp K/K mice along with downstream target gene expression for enzymes within the fatty acid biosynthesis pathway.…”

Targeted disruption of steroidogenic acute regulatory protein D4 leads to modest weight reduction and minor alterations in lipid metabolism

“…Initial studies of PCTP disruption showed no difference in phospholipid metabolism ( 23 ). However, when pushed with a lithogenic diet, PCTP knockouts showed an impaired excretion of lipid into bile and an improper balance in the bile of cholesterol to phospholipids ( 24,25 ). Mice with MLN64 mutations also have no apparent abnormalities in lipid metabolism or storage when pushed with a chow, highcholesterol, or high-fat diet ( 26 ).…”

Mice lacking Pctp /StarD2 exhibit increased adaptive thermogenesis and enlarged mitochondria in brown adipose tissue

“…This study was motivated by the observation that Pctp Ϫ / Ϫ mice utilize fatty acids almost exclusively as an energy substrate ( 8 ). Because in small animals, brown fat consumes half or more of calories and oxygen ( 13 ), we reasoned that BAT physiology might yield key insights into metabolic regulation in Pctp Ϫ / Ϫ mice.…”

“…Wild-type and Pctp Ϫ / Ϫ littermate control mice on an FVB/NJ genetic background ( 8 ) were housed (two to fi ve mice/cage) in an animal facility with a 12 h light/dark cycle and maintained on a standard rodent diet 5001 (LabDiets, St. Louis, MO). The temperature of the animal facility was maintained at 22 ± 1°C.…”

“…Gene-specifi c primers were designed using the web-based software Primer3 (http://frodo.wi.mit.edu/cgi-bin/primer3/ primer3_www.cgi) and are listed in supplementary Table I. The L32 ribosome protein (Rpl32) was used as an invariant gene ( 8 ).…”