Conclusion: These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance. (HEPATOLOGY click here 2011;) Phosphatidylcholine transfer protein (PC-TP) is a soluble, highly specific lipid binding protein with accentuated expression in the liver.1 PC-TP was identified, purified, and named based on its capacity to catalyze the intermembrane exchange of phosphatidylcholines in vitro.2 According to its characteristic lipid binding pocket that accommodates a single phosphatidylcholine

molecule,3 PC-TP has been designated StARD2 within the steroidogenic acute regulatory protein-related transfer (START) domain superfamily.3, 4 Specificity for binding phosphatidylcholines is conferred by a uniquely structured phosphorylcholine head group binding site within the lipid

binding pocket of PC-TP.3 Interestingly, evidence for a biological role ABT-888 cell line for PC-TP in lipid transport in vivo is generally lacking,5 and we have instead reported the unanticipated finding that PC-TP regulates glucose metabolism6: Livers of chow-fed Pctp−/− mice exhibit increased insulin sensitivity, CYTH4 as evidenced by profound decreases in hepatic glucose production under hyperinsulinemic euglycemic clamp conditions.6 Although the molecular mechanism is not fully understood,

PC-TP may control hepatic glucose homeostasis in response to variations in the fatty acyl composition of membrane phospholipids.5 Type 2 diabetes is characterized by excess hepatic glucose production due to insulin resistance, commonly in the setting of obesity.7 As evidenced by coding region polymorphisms in both humans and mice, PC-TP may play a pathogenic role. A Glu10Ala substitution in human subjects in the Quebec Family Study was correlated with a 3-fold lower risk of the atherogenic small dense low-density lipoprotein (LDL) phenotype,8 which is commonly associated with insulin resistance.9 In New Zealand Obese (NZO) mice, an Arg120His substitution in PC-TP appeared to play a protective role against the development of obesity-associated type 2 diabetes.5, 10 The current study was designed to provide a direct test of whether Pctp−/− mice are resistant to high-fat diet-induced increases in hepatic glucose metabolism and whether small molecule inhibition of PC-TP would recapitulate this phenotype.