PPAR alpha, more than PPAR delta, mediates the hepatic and skeletal muscle alterations induced by the PPAR agonist GW0742.
Therapeutic use of certain peroxisome proliferator-activated receptor (PPAR) alpha agonists (fibrates) for the treatment of dyslipidemia has infrequently been associated with the untoward side effect of myopathy. With interest in PPAR-delta as a therapeutic target, this study assessed whether a PPAR-delta agonist induced similar hepatic and skeletal muscle alterations as noted with some fibrates. PPAR-alpha null (KO) and corresponding wild-type (WT) mice were administered toxicological dosages of a potent PPAR-delta agonist tool ligand (GW0742; which also has weak PPAR-alpha agonist activity) or a potent PPAR-alpha agonist (WY-14,643) for 10 days. Increases in liver weights and clinical chemistry indicators of skeletal muscle damage and/or liver injury were more pronounced in WT mice compared with KO mice administered the PPAR-delta agonist. Likewise, the incidence and severity of skeletal myopathy were greater in WT mice given GW0742 compared with KO mice. Ultrastructural and immunohistochemical analyses revealed significant peroxisome proliferation in muscle and liver of WT mice treated with each agonist; however, KO animals showed little or no evidence of hepatic and muscle peroxisome proliferation. PMP-70 protein expression in liver was consistent with these results. The hepatomegaly, hepatic and skeletal muscle peroxisome proliferation, and skeletal myopathy induced by this PPAR-delta ligand was predominantly mediated by its cross-activation of PPAR-alpha, though PPAR-delta agonism contributed slightly to these effects.
Faiola
Brenda
B
Safety Assessment Department, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. Brenda.x.Faiola@gsk.com
Falls
James Greg
JG
Peterson
Richard A
RA
Bordelon
Nancy R
NR
Brodie
Thomas A
TA
Cummings
Connie A
CA
Romach
Elizabeth H
EH
Miller
Richard T
RT
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006529:Hepatomegaly / Q000139:chemically induced / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism; D009929:Organ Size; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000633:toxicity*; D013844:Thiazoles / Q000633:toxicity*; D010636:Phenols; D013438:Sulfhydryl Compounds
D047493:PPAR alpha; D047494:PPAR delta; D011743:Pyrimidines; 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; C006253:pirinixic acid