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American Liver Foundation
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American Liver Foundation Postdoctoral Research Fellowship Award
Brigham and Women’s Hospital, Boston, Massachusetts
“Regulation of Hepatic Glucose Homeostasis by Phosphatidylcholine-Transfer Protein (PC-TP) and Thioesterase Superfamily Member 2 (Them2)”
Non-alcoholic fatty liver (NAFLD) is a pathologic accumulation of fat in the liver, which can lead to cirrhosis when associated with inflammation of the liver. Obesity and type 2 diabetes are the most common nutritionally-related disorders in Western populations that are frequently associated with NAFLD. Obesity induced resistance to insulin action is the primary pathophysiological defect that predisposes to type 2 diabetes and NAFLD. Because current management options remain limited, identification of new regulatory pathways that govern the metabolic response to insulin should serve to identify novel opportunities for pharmacologic intervention. Dr. David E. Cohen’s laboratory, where Dr. Ersoy is conducting his postdoctoral fellowship, has identified two novel interacting proteins, Phosphatidylcholine-transfer protein (PC-TP) and Thioesterase superfamily member 2 (THEM2), which are enriched in the liver and appear to play key roles in the control of glucose and lipid homeostasis within hepatocytes. Mice lacking the expression of either protein exhibit increased hepatic insulin sensitivity and are protected against diet-induced type 2 diabetes. The goal of Dr. Ersoy's research is to characterize the molecular mechanisms by which PC-TP and THEM2 regulate hepatic glucose metabolism. The rationale is that the identification of a novel protein complex that regulates hepatic insulin sensitivity could lead to the identification of new therapeutic targets for the treatment of NAFLD and type 2 diabetes. His preliminary studies have identified Tuberous Sclerosis Complex 2 (TSC2), which together with TSC1 regulates mTOR, as a potential site within the insulin signaling that is regulated by PC-TP and THEM2. His experiments have further revealed that THEM2 may regulate endoplasmic reticulum stress (ER), which is mechanistically linked to hepatic insulin resistance. Guided by these preliminary data, the central hypothesis of this research plan is that PC-TP and THEM2 regulate hepatic glucose homeostasis through interactions with TSC2, which will be tested in two specific aims: 1) Define the mechanisms by which PC-TP and THEM2 interact with TSC2 to regulate insulin signaling; 2) Characterize the roles of PC-TP and THEM2 in the control of ER stress. In aim 1, the effect of siRNA-mediated silencing of PC-TP and THEM2 expression on the insulin signaling will be determined by measuring the activity of key effectors of the insulin signaling pathway in cell culture. Pharmacological inhibitors targeting various steps in the insulin signaling pathway will be used to localize the point of regulation by PC-TP and THEM2. As suggested by preliminary observations, a direct interaction between PC-TP and TSC2 interacting domains will be tested using pull-down assays. The relevance of TSC2 in the PC-TP and THEM2 mediated regulation of insulin signaling will be probed in cell lines lacking TSC2 expression. It is anticipated that PC-TP, THEM2 and TSC2 will form a novel protein complex that serves to regulate hepatocellular insulin signaling. In aim 2, the chemical reagent tunicamycin in cell culture and a prolonged high-fat diet in Pctp-/- and Them2-/- mice will be utilized to induce ER stress. The roles of PC-TP and THEM2 in the induction of ER stress will be assessed according to standard ER stress markers. The results of these experiments should clarify whether PC-TP and THEM2 regulate hepatic insulin sensitivity by modulating ER stress. The characterization of a novel regulatory protein complex that regulates hepatic insulin sensitivity should contribute to rational strategies for the management of NAFLD and type 2 diabetes.