Peroxisome Proliferator-Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Objective-Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR alpha is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPAR alpha agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPAR alpha therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo-and heterozygous PPAR alpha-deficient mice, the consequences of quantitative variations of PPAR alpha gene levels and their response to the synthetic PPAR alpha agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. Methods and Results-Wild-type ((+/+)), heterozygous ((+/-)), and homozygous (-/-) PPAR alpha-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPAR alpha-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPAR alpha+/+ and PPAR alpha+/- apoE2-KI mice, indicating a role of PPAR alpha in liver protection. Moreover, PPAR alpha expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPAR alpha+/+ and PPAR alpha+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPAR alpha gene were required. Surprisingly, atherosclerosis development was not significantly different among PPAR alpha+/+, PPAR alpha+/-, and PPAR alpha-/- apoE2-KI mice. However, PPAR alpha gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. Conclusion-These results demonstrate a necessary but quantitatively different role of PPAR alpha in the modulation of liver metabolism, inflammation, and atherogenesis. (Arterioscler Thromb Vasc Biol. 2011; 31:1573-1579.)