OBJECTIVEThe peroxisome proliferator–activated receptor-γ coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1α activity affect metabolism and energy homeostasis has yet to be determined.RESEARCH DESIGN AND METHODSTo identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1α levels, we used the Cre/Lox system to create mice heterozygous for PGC-1α specifically within the liver (LH mice).RESULTSThese mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial β-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes.CONCLUSIONSThese data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1α levels, underlining the importance of tightly regulated PGC-1α expression in the maintenance of lipid homeostasis and glucose metabolism.

The Star (steroidogenic acute regulatory protein)-related transfer (START) domain superfamily is characterized by a distinctive lipid-binding motif. START domains typically reside in multidomain proteins, suggesting their function as lipid sensors that trigger biological activities. Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is an example of a START domain minimal protein that consists only of the lipidbinding motif. PC-TP, which binds phosphatidylcholine exclusively, is expressed during embryonic development and in several tissues of the adult mouse, including liver. Although it catalyzes the intermembrane exchange of phosphatidylcholines in vitro, this activity does not appear to explain the various metabolic alterations observed in mice lacking PC-TP. Here we demonstrate that PC-TP function may be mediated via interacting proteins. Yeast two-hybrid screening using libraries prepared from mouse liver and embryo identified Them2 (thioesterase superfamily member 2) and the homeodomain transcription factor Pax3 (paired box gene 3), respectively, as PC-TP-interacting proteins. These were notable because the START domain superfamily contains multidomain proteins in which the START domain coexists with thioesterase domains in mammals and with homeodomain transcription factors in plants. Interactions were verified in pulldown assays, and colocalization with PC-TP was confirmed within tissues and intracellularly. The acyl-CoA thioesterase activity of purified recombinant Them2 was markedly enhanced by recombinant PC-TP. In tissue culture, PC-TP coactivated the transcriptional activity of Pax3. These findings suggest that PC-TP functions as a phosphatidylcholine-sensing molecule that engages in diverse regulatory activities that depend upon the cellular expression of distinct interacting proteins. Phosphatidylcholine transfer protein (PC-TP)5 is a soluble lipid-binding protein with high specificity for phosphatidylcholines (1, 2). Whereas PC-TP promotes intermembrane exchange of phosphatidylcholines in vitro, its physiological function in vivo is not well understood (3). Studies in tissue culture and knock-out mice have demonstrated physiological roles for PC-TP in hepatobiliary lipid homeostasis, reverse cholesterol transport, and high density lipoprotein metabolism (3). However, these effects do not appear to be fully explained by the phosphatidylcholine transfer activity of PC-TP.PC-TP (also known as StarD2) is a member of a steroidogenic acute regulatory protein-related transfer (START) domain protein superfamily (4). START domains are conserved motifs that bind hydrophobic ligands. Proteins that contain START domains participate in intracellular lipid transport, lipid metabolism, and cellular signaling (5-7). START domain proteins are expressed from bacteria to higher organisms but are most numerous in plants (8).START domains largely reside within multidomain proteins, suggesting that binding of a hydrophobic ligand might regulate activity of another domain within the same protein. By cont...

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.