Abstract 17101: Targeting of Heparin-Binding EGF-Like Growth Factor (HB-EGF) Effectively Protected Against Hyperlipidemia-Associated Vascular and Hepatic Inflammations

Abstract

Introduction: Obesity and hepatic VLDL overproduction are key risk factors for the development of dyslipidemia and metabolic inflammatory diseases including atherosclerosis and non-alcoholic fatty liver disease (NAFLD). HB-EGF is a representative mediator for sustained EGFR transactivation under diverse oxidative stress environments including central obesity. A previous report showed that, in C57BL/6 mice, an injection of recombinant HB-EGF significantly increased apoB and TG secretion from the liver; in contrast, HB-EGF antisense oligonucleotide (ASO) administration induced a significant suppression of the hepatic VLDL secretion. Hypothesis: In this study, we tested the hypothesis, which was, that HB-EGF is an autonomous stimulator for the hepatic VLDL production in the liver, which would result in the development of hypertriglyceridemia, causing metabolic inflammatory diseases when under obese and over-nutrition. Methods and Results: In liver-derived cell line HepG2, recombinant HB-EGF treatment induced an autonomous increase of apoB production in the cells. In LDLR deficient mice under a western diet, which showed a list of metabolic syndrome phenotypes, HB-EGF ASO administration induced an effective downregulation of circulatory VLDL and TG level. The HB-EGF ASO administration also showed effective protection against atherosclerosis and non-alcoholic steatohepatitis (NASH) phenotypes in the mouse model. Conclusions: The results suggest that HB-EGF is a positive stimulator of hepatic VLDL production that may cause hypertriglyceridemia under obese and over-nutrition. It was also demonstrated that HB-EGF targeting could be an effective approach to prevent and reverse vascular and hepatic inflammations as shown in a mouse model. Figure: LDLR deficient mice under western diet were treated with control and HB-EGF ASOs for 12 weeks. CD68 positive cell content and inflammatory gene MCP1 transcription level in liver were compared.