Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production
Year: 2011
Type: article
Abstract: UNLABELLED: Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp-/- mice are protected against diet-induced increases in hepatic glucose production and that small molecule inhibition of PC-TP recapitulates this phenotype. Pctp-/- and wildtype mice were subjected to high-fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high-fat diet-induced increases in hepatic glucose production were markedly attenuated in Pctp-/- mice. Small molecule inhibitors of PC-TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high-fat-fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC-TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high-fat feeding, but had no activity in Pctp-/- mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin-sensitizing agents, the inhibitor promoted insulin-independent phosphorylation of key insulin signaling molecules. CONCLUSION: These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance.
Source: Hepatology
DOI: 10.1002/hep.24393
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: American Liver Foundation, Brigham and Women's Hospital, Harvard University, Harvard Catalyst, National Institutes of Health, Harvard Digestive Diseases Center, Harvard University, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G109503089, G1425212935, MOLECULAR PHYSIOLOGY OF BILIARY LIPID SECRETION, Regulation of Hepatic Glucose Fluxes, G2496518617, Harvard Clinical and Translational Science Center (UL1), G4523881014, Mechanisms of complement induced endothelial dysfunction, Phospholipid-Mediated Metabolic Control in the Pathogenesis of NAFLD, Regulation of Hepatic Lipid and Glucose Metabolism by PC-TP/StarD2, G831791976, G9000038285, G9000092807, Training in Pediatric Gastroenterology, Hepatology, and Nutrition, Integrated Epithelial and Muscosal Biology, Lipid-Mediated Control of Acetyl-CoA Metabolism in the Pathogenesis of NAFLD, G923503880, Innate Immunity and Cardiovascular Function
OpenAlex ID: W2135339265