title: 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-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα 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 PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice.
  
  
  RESULTS
  Wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPARα-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/- apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/-, and PPARα-/- apoE2-KI mice. However, PPARα 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 PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
authors.affiliation: University Lille Nord de France, Lille, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lalloyer
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Morgane
authors.initials: M
authors.lastname: Baron
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caron
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Vallez
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vanhoutte
authors.forename: Eric
authors.initials: E
authors.lastname: Baugé
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
authors.forename: Marten
authors.initials: M
authors.lastname: Hofker
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D053329:Apolipoprotein E2; D000960:Hypolipidemic Agents; D008055:Lipids; D047493:PPAR alpha; D011345:Fenofibrate