Fibrate treatment does not modify the expression of acyl coenzyme A oxidase in human liver

Background and objectives: Fibrates induce hepatic peroxisome proliferation and carcinogenesis in rodents by activating peroxisome proliferator-activated receptor alpha (PPARalpha). There is no conclusive evidence that humans are unresponsive to peroxisome proliferation, and concern exists about the long-term safety of fibrate treatment. Methods: In a university hospital setting, 48 patients with uncomplicated gallstones and a serum level of low-density lipoprotein cholesterol greater than 130 mg/dL were randomly assigned to open-label treatment with bezafibrate (400 mg/d), fenofibrate (200 mg/d), gemfibrozil (900 mg/d), or placebo for 8 weeks before elective cholecystectomy. Serum samples for lipid determinations were obtained at baseline and before surgery. A liver specimen was obtained at operation, and the relative levels of messenger ribonucleic acid (mRNA) for the wild and truncated forms of PPARalpha, acyl coenzyme A oxidase, liver carnitine palmitoyltransferase I, apolipoprotein A-I, and stearoyl coenzyme A desaturase were determined. Results. Fenofibrate, bezafibrate, and gemfibrozil reduced plasma low-density lipoprotein cholesterol levels by 22% (P=.009), 14% (P=.042), and 11% (not significant), respectively. Plasma triglyceride levels decreased significantly (24%-36%; P<.05), whereas high-density lipoprotein cholesterol levels rose non-significantly after treatment with the 3 fibrates. Except for a 35% increase of apolipoprotein A-I mRNA after fenofibrate administration (P<.05), none of the individual fibrates induced significant changes in the mRNAs tested, although as a group they increased the mRNA for liver carnitine palmitoyltransferase I by 40% (P=.08; marginally significant). Conclusions: Fibrate administration to humans at pharmacologic doses able to activate PPARalpha and to induce a hypolipidemic effect does not increase the hepatic expression of acyl coenzyme A Oxidase, a well-known marker of peroxisome proliferation in rodents.