Abstract
Abstract Objective : Peroxisome Proliferator -Activated Receptor D (PPAR D ) is a ligand -activated transcription factor which controls lipid metabolism and inflammation. PPAR D is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPAR D agonists on atherosclerosis in mice yielded conflicting results and the implication of PPAR D therein has not been assessed. The human apoE2 knock -in (apoE2 -KI) mouse is a model of mixed dyslipidemia, atherosclerosis and non -alcoholic steatohepatitis ( NASH). T he aim of this study was, using homo - and heterozygous PPAR D -deficient mice, to analyze the consequences of quantitative variations of PPAR D gene levels and its response to the synthetic PPAR D agonist fenofibrate, o n NASH and atherosclerosis in apoE2 -KI mice. Metho ds and results : W ildtype (+/+), heterozygous (+/ -) and homozygous ( -/-) PPAR D -deficient mice in the apoE2 -KI background were generated and submitted to a western diet supplemented or not with fenofibrate. Western diet -fed PPAR D -/- apoE2 -KI mice displayed a n aggravation of liver steatosis and inflammation compared to PPAR D +/+ and PPAR D +/ - apoE2 -KI mice, indicating a role of PPAR D in liver protection. Moreover, PPAR D expression was required for t he fenofibrate -induced protection against NASH . Interestingly , fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPAR D +/+ and PPAR D +/ - apoE2 -KI mice, whereas, for a maximal anti -inflammatory response, both alleles of the PPAR D gene were required. Surprisingly, atherosclerosis development was not significantly different between PPAR D +/+, PPAR D +/ - and PPAR D -/- apoE2 -KI mice. However, PPAR D gene level determined both the anti -atherosclerotic and vascular anti -inflammatory responses to fenofibrate in a dose -dependent manner. Conclusions: These results demonstrate a necessary, but quantitatively different role of PPAR D in the modulation of liver metabolism, inflammation and atherogenesis. Keywords: PPAR D , fatty liver disease, atherosclerosis, inflammation, lipid metabolism, murine model
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