Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.

ABSTRACT: OBJECTIVE: Peroxisome proliferator-activated receptor-? (PPAR?) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR? is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPAR? agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPAR? 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?-deficient mice, the consequences of quantitative variations of PPAR? gene levels and their response to the synthetic PPAR? agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. METHODS AND RESULTS: Wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PPAR?-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?-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPAR?+/+ and PPAR?+/- apoE2-KI mice, indicating a role of PPAR? in liver protection. Moreover, PPAR? expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPAR?+/+ and PPAR?+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPAR? gene were required. Surprisingly, atherosclerosis development was not significantly different among PPAR?+/+, PPAR?+/-, and PPAR?-/- apoE2-KI mice. However, PPAR? 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 PPAR? in the modulation of liver metabolism, inflammation, and atherogenesis.

SUBMITTER: Lalloyer F 

PROVIDER: S-EPMC3327645 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature