The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE−/−FXR−/− Mice
Yenna Lee, Bo-Rahm Kim, Geun-Hyung Kang, Gwan Jae Lee, Young Joo Park, Haeryoung Kim, Hak Chul Jang, Sung Hee Choi
Abstract
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: <i>En face</i> 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 (<i>ApoE</i>)<sup>−/−</sup> and <i>ApoE</i><sup>−/−</sup><i>FXR</i><sup>−/−</sup> mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.Results: Compared with <i>ApoE</i><sup>−/−</sup> mice, <i>ApoE</i><sup>−/−</sup><i>FXR</i><sup>−/−</sup> 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 <i>FAS</i>, <i>ApoC2</i>, <i>TNFα</i>, <i>IL-6</i> (liver), <i>ATGL</i>, <i>TGH</i>, <i>HSL</i>, and <i>MGL</i> (adipocytes), and decreased mRNA expressions of <i>CPT2</i> (liver) and <i>Tfam</i> (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 <i>ApoE</i><sup>−/−</sup><i>FXR</i><sup>−/−</sup> mice, in association with increased mRNA expression of <i>CD36</i> and <i>FATP</i> and decreased expression of <i>ApoC2</i> and <i>ApoC3</i> (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.