COBRE Pilot Project for Sangderk Lee: Center of Research in Obesity and Cardiovascular Disease

Elevation of ApoB-containing lipoproteins in the blood stream is a risk factor for atherosclerosis. The heparin binding epidermal growth factor-like growth factor (HBEGF) mediates EGFR transactivation under oxidative stress including hyperlipidemia. The goal of the proposed studies is to examine the working mechanism of HBEGF targeting using antisense oligonucleotide (ASO) to repress hyperlipidemia and atherosclerosis and to gain a better understanding of the mechanism of action of HBEGF in regulating lipid metabolism. Our preliminary studies showed that HBEGF ASO injection showed remarkable repression of hyperlipidemia and atherosclerosis in LDLR KO mice under high fat diet feeding. The ASO injection efficiently downregulated total cholesterol, triglyceride (TG), VLDL, and LDL levels in the blood stream with the most pronounced effect on VLDL particles. HBEGF ASO injection resulted in suppression of sterol synthesis genes that are mainly regulated by sterol regulatory element binding proteins (SREBPs) in the liver. From these observations, we hypothesize that HBEGF is an unappreciated regulator of hepatic lipid metabolism in the liver and a potential target for lipid lowering. In Specific Aim1, to identify the mechanism of HBEGF signaling in regulating hyperlipidemia and atherosclerosis, we will test the effect of liver-specific HBEGF knockout on the induction of hyperlipidemia and lesion development by high fat diet feeding. In Specific Aim 2, using liver cell lines, we will decipher which HBEGF signaling pathway regulates SREBP function for lipid synthetic gene expressions in the liver. In this study, we demonstrate for the first time that the HBEGF, which is an EGFR ligand, is a key regulator for the lipid and lipoprotein metabolism in the liver tissue. Considering the remarkable lipid-lowering effects of HBEGF ASO as shown in ASO study, the targeting of HBEGF could make substantial impact in treating patients with hyperlipidemia and atherosclerotic dyslipidemia induced by obesity and metabolic syndrome.