The Effect of PPAR Agonists on Atherosclerosis and Non-Alcoholic Fatty Liver Disease in ApoE-/-FXR-/- Mice

Abstract

Farnesoid X receptor (FXR), a bile acid activated nuclear receptor, is a potent regulator for glucose and lipid metabolism as well as for bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements including atherosclerosis, but discrepancies exist regarding the implications of its deficiency on the development of atherosclerosis. <br/> This study aims to investigate the role of FXR in atherosclerosis by comparing mouse models of ApoE deficiency with mouse models of both ApoE and FXR deficiency. <br/> ApoE-/-FXR-/- mice showed more severe atherosclerosis compared with ApoE-/- mice, associated with increased plasma levels of cholesterol, LDL-cholesterol, and triglycerides. Histologic examination of the liver demonstrated increased fat deposition in the form of macrovesicular steatosis. Quantitative reverse transcriptase analysis (RT-PCR) revealed increased mRNA expressions of FAS, ApoC2, TNFα, IL-6, and decreased mRNA expression of CPT2 in liver, and increased mRNA expressions of genes related to lipolysis (ATGL, TGH, HSL, MGL) in adipose tissue. PPARs (peroxisome proliferator activated receptors) are well known nuclear receptors related to bile acid, lipid, and glucose metabolism and insulin resistance, acting mainly in liver an adipose tissue. <br/> Based on the similarities in the metabolic actions of FXR and PPARs, it was hypothesized that PPAR agonists can ameliorate the metabolic derangements caused by FXR deficiency. Consequently it was found that fenofibrate, a PPARα agonist, reversed the atherosclerosis and hepatic steatosis, caused by additional FXR deficiency to ApoE deficient mice, associated with decreased plasma triglyceride levels. Quantitative RT-PCR analysis revealed increased mRNA expressions of CD36 and FATP1, and decreased mRNA expressions of Apo C2 and ApoC3 in liver. On the contrary, pioglitazone, a PPARγagonist, was unable to make significant improvements in both atherosclerosis and hepatic steatosis. <br/> In conclusion, loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which may be reversed by PPARα agonist through induction of triglyceride hydrolysis and β-oxidation of fatty acids.<br/>