title: Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein.
abstract: Dyslipidemia and inflammation play an important role in the pathogenesis of cardiovascular and liver disease. Fenofibrate has a well-known efficacy to reduce cholesterol and triglycerides. Combination with statins can ameliorate hypolipidemic and anti-inflammatory effects of fibrates. In the current study, we tested the anti-inflammatory and metabolic effects of fenofibrate alone and in combination with rosuvastatin in a model of inflammation and metabolic syndrome, using spontaneously hypertensive rats expressing the human C-reactive protein transgene (SHR-CRP transgenic rats). SHR-CRP rats treated with fenofibrate alone (100 mg/kg body weight) or in combination with rosuvastatin (20 mg/kg body weight) vs. SHR-CRP untreated controls showed increased levels of proinflammatory marker IL6, increased concentrations of ALT, AST and ALP, increased oxidative stress in the liver and necrotic changes of the liver. In addition, SHR-CRP rats treated with fenofibrate, or with fenofibrate combined with rosuvastatin vs. untreated controls, exhibited increased serum triglycerides and reduced HDL cholesterol, as well as reduced hepatic triglyceride, cholesterol and glycogen concentrations. These findings suggest that in the presence of high levels of human CRP, fenofibrate can induce liver damage even in combination with rosuvastatin. Accordingly, these results caution against the possible hepatotoxic effects of fenofibrate in patients with high levels of CRP.
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic. jsilhavy@biomed.cas.cz.
authors.forename: V
authors.initials: V
authors.lastname: Škop
authors.forename: J
authors.initials: J
authors.lastname: Trnovská
authors.forename: O
authors.initials: O
authors.lastname: Oliyarnyk
authors.forename: I
authors.initials: I
authors.lastname: Marková
authors.forename: H
authors.initials: H
authors.lastname: Malínská
authors.forename: L
authors.initials: L
authors.lastname: Kazdová
authors.forename: V
authors.initials: V
authors.lastname: Zídek
authors.forename: V
authors.initials: V
authors.lastname: Landa
authors.forename: P
authors.initials: P
authors.lastname: Mlejnek
authors.forename: M
authors.initials: M
authors.lastname: Šimáková
authors.forename: M
authors.initials: M
authors.lastname: Kůdela
authors.forename: M
authors.initials: M
authors.lastname: Pravenec
authors.forename: J
authors.initials: J
authors.lastname: Šilhavý
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology*; D011345:Fenofibrate / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008111:Liver Function Tests; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic; D000068718:Rosuvastatin Calcium / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D000068718:Rosuvastatin Calcium; D002097:C-Reactive Protein; D013230:Stearoyl-CoA Desaturase; C000594769:stearoyl-CoA desaturase SCD-1, rat; D005947:Glucose; D011345:Fenofibrate