title: Generation and characterization of a humanized PPARδ mouse model.
abstract: OBJECTIVE
  Humanized mice for the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ), termed PPARδ knock-in (PPARδ KI) mice, were generated for the investigation of functional differences between mouse and human PPARδ and as tools for early drug efficacy assessment.
  
  
  METHODS
  Human PPARδ function in lipid metabolism was assessed at baseline, after fasting or when challenged with the GW0742 compound in mice fed a chow diet or high-fat diet (HFD).
  
  
  RESULTS
  Analysis of PPARδ mRNA levels revealed a hypomorph expression of human PPARδ in liver, macrophages, small intestine and heart, but not in soleus and quadriceps muscles, white adipose tissue and skin. PPARδ KI mice displayed a small decrease of high-density lipoprotein-cholesterol whereas other lipid parameters were unaltered. Plasma metabolic parameters were similar in wild-type and PPARδ KI mice when fed chow or HFD, and following physiological (fasting) and pharmacological (GW0742 compound) activation of PPARδ. Gene expression profiling in liver, soleus muscle and macrophages showed similar gene patterns regulated by mouse and human PPARδ. The anti-inflammatory potential of human PPARδ was also similar to mouse PPARδ in liver and isolated macrophages.
  
  
  CONCLUSIONS
  These data indicate that human PPARδ can compensate for mouse PPARδ in the regulation of lipid metabolism and inflammation. Overall, this novel PPARδ KI mouse model shows full responsiveness to pharmacological challenge and represents a useful tool for the preclinical assessment of PPARδ activators with species-specific activity.
authors.affiliation: Université Lille Nord de France, Lille, France.
authors.forename: B
authors.initials: B
authors.lastname: Gross
authors.forename: N
authors.initials: N
authors.lastname: Hennuyer
authors.forename: E
authors.initials: E
authors.lastname: Bouchaert
authors.forename: C
authors.initials: C
authors.lastname: Rommens
authors.forename: D
authors.initials: D
authors.lastname: Grillot
authors.forename: H
authors.initials: H
authors.lastname: Mezdour
authors.forename: B
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D059305:Diet, High-Fat / Q000379:methods; D005215:Fasting / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D018076:DNA, Complementary; D008075:Lipoproteins, HDL; D047494:PPAR delta; D012333:RNA, Messenger; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds