OBJECTIVE: Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARalpha is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARalpha agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARalpha 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 PPARalpha-deficient mice, the consequences of quantitative variations of PPARalpha gene levels and their response to the synthetic PPARalpha agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. METHODS AND RESULTS: Wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PPARalpha-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPARalpha-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARalpha+/+ and PPARalpha+/- apoE2-KI mice, indicating a role of PPARalpha in liver protection. Moreover, PPARalpha expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARalpha+/+ and PPARalpha+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARalpha gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARalpha+/+, PPARalpha+/-, and PPARalpha-/- apoE2-KI mice. However, PPARalpha gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. CONCLUSIONS: These results demonstrate a necessary but quantitatively different role of PPARalpha in the modulation of liver metabolism, inflammation, and atherogenesis.