Abstract 12525: Synergistic Effects of Pitavastatin and Pemafibrate on Hepatic Steatosis and Inflammation in Ldlr +/- Mice Fed Fat Diet

Abstract

Introduction: The combination therapy of statin, ezetimibe and PCSK9 inhibitors enables us to reduce serum LDL-C and risk of atherosclerotic diseases. However, there remain patients who cause cardiovascular diseases. Recently, it has been reported that nonalcoholic fatty liver disease (NAFLD) might be a background for cardiovascular diseases. However, there are few reports on the combination therapy of statin and pemafibrate on hepatic steatosis and inflammation. Hypothesis: The aim of this study is to examine the impact of statin and/or pemafibrate on hepatic lipid contents and inflammatory gene expression in Ldlr +/- mice. Methods: Eight to ten weeks old male Ldlr +/- mice were used. Mice were fed high fat diet (HFD) ± 0.01% pitavastatin ± 0.00003% pemafibrate for four weeks. Serum lipids and liver histology/ lipid contents/ mRNA expression in four groups were examined. Results: Pemafibrate reduced serum triglycerides, particularly chylomicron and VLDL fractions, and increased HDL-C as previously reported. Hepatic triglyceride was unchanged, and very importantly, hepatic cholesterol and free-cholesterol were decreased with pitavastatin + pemafibrate compared to pitavastatin (pitavastatin vs pitavastatin + pemafibrate: cholesterol; 13.5±4.7 vs 9.4±1.9 mg/g of liver, P<0.01, free-cholesterol; 10.4±4.8 vs 6.9±1.4 mg/g of liver, P<0.01). The addition of pemafibrate resulted in a 46% increase in Cyp7a1 mRNA expression, suggesting that cholesterol in liver was reduced due to enhanced cholesterol excretion. Tnfa mRNA in liver was reduced by 62% and F4/80 staining of the liver showed decreased macrophage infiltration. Conclusions: Adding pemafibrate to pitavastatin did not alter hepatic triglyceride, however decreased cholesterol and free-cholesterol and improved inflammatory gene responses in liver, suggesting that the synergistic effect of pitavastatin and pemafibrate may be beneficial in NAFLD related atherosclerotic patients.