Abstract 15512: The Hepatic Lipid Type and Content Had an Impact on Hepatic Inflammation and Fibrosis in Streptozotocin-Induced Diabetic Mice

Abstract

Introduction: It has been reported that nonalcoholic fatty liver disease is an independent risk factor for cardiovascular diseases. We have recently demonstrated that diet-induced steatohepatitis was associated with cardiac dysfunction and those were improved by the selective PPARα modulator, pemafibrate in wild type mice. Hypothesis: The aim of the study is to characterize the relationship between hepatic lipid content and inflammation, induced by two type of diets in diabetic mice model and to test the effect of pemafibrate on those. Methods: C57BL/6 mice were injected with streptozotocin (STZ) (40mg/kg for 4 days). Mice whose ad libitum blood glucose were 200-350mg/dl, were used as diabetic mice. In 11-week-old STZ induced diabetic mice were administered wild high fat/high cholesterol diet (WD group) or high fat/high cholesterol/ high sucrose/bile acids diet (NASH group), with or without pemafibrate for 12 weeks. Lipid profiles, liver cytokines, hepatic mRNA, liver histology were investigated. Results: Total cholesterol and unesterified cholesterol were significantly more accumulated in the NASH group compared to the WD group. Triglyceride were not changed between two groups. F4/80 positive area and sirius-red positive area were significantly increased in the NASH group compared to the WD group. Inflammatory cytokines such as Tnfa, Il1b and fibrosis associated genes Col1a1 and Col1a2 were also significantly increased in the NASH group, suggesting the presence of active inflammation and fibrosis in the NASH group. By co-administration with pemafibrate, serum HDL-C level was increased by 48.7% and the non-HDL-C level was decreased by 31.4% in the NASH/pemafibrate group. Importantly, total cholesterol and unesterified cholesterol were markedly decreased in the NASH/pemafibrate group. Along with those, F4/80 positive area and sirius-red positive area were decreased in the NASH/pemafibrate group by more than 50%. Hepatic Tnfa expression was decreased by 56.3% and Tgfb, Col1a1, Col1a2 was significantly decreased. Conclusions: Our study demonstrated that more total cholesterol and unesterified accumulation induced hepatic inflammatory responses and fibrosis in the diabetic mice and pemafibrate had the beneficial impacts on those.