The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE(−/−)FXR(−/−) Mice

BACKGROUND: Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency. METHODS: En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)(−/−) and ApoE(−/−)FXR(−/−) mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice. RESULTS: Compared with ApoE(−/−) mice, ApoE(−/−)FXR(−/−) mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE(−/−)FXR(−/−) mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver). CONCLUSION: Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.