(Circulation. 1999;99:2445-2451.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Beneficial Effects of Fibrates on Apolipoprotein A-I Metabolism Occur Independently of Any Peroxisome Proliferative Response
From U325 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, France (N.H., P.P., J.C.F., C.F., B.S.); the Department of Clinical Biology, Division of Biochemistry, University of Bergen, Haukeland Hospital, Bergen, Norway (L.M., R.K.B.); the Cardiovascular Department, CRVA Rhône-Poulenc Rorer-Gencell, Vitry-sur-Seine, France (D.B., N.D.); and INRA, Jouy en Josas, France (L.M.H.).
Correspondence to Bart Staels, INSERM U325, Institut Pasteur de Lille, 1, rue du Prof Calmette, 59019 Lille Cedex, France. E-mail bart.staels{at}pasteur-lille.fr
Background—In humans, fibrates
are frequently used normolipidemic drugs. Fibrates act by regulating
genes involved in lipoprotein metabolism via activation of
the peroxisome proliferator-activated receptor-
(PPAR) in
liver. In rodents, however, fibrates induce a peroxisome proliferation,
leading to hepatomegaly and possibly hepatocarcinogenesis. Although
this peroxisome proliferative response appears not to occur in humans,
it remains controversial whether the beneficial effects of fibrates on
lipoprotein metabolism can occur dissociated from such
undesirable peroxisomal response. Here, we assessed the influence of
fenofibrate on lipoprotein metabolism and peroxisome
proliferation in the rabbit, an animal that, contrary to rodents and
similar to humans, is less sensitive to peroxisome
proliferators.
Methods and Results—First, we demonstrate that in normal rabbits, fenofibrate given at a high dose for 2 weeks does not influence serum concentrations or intestinal mRNA levels of the HDL apolipoprotein apoA-I. Therefore, the study was continued with human apoA-I transgenic rabbits that overexpress the human apoA-I gene under control of its homologous promoter, including its PPAR-response elements. In these animals, fenofibrate increases serum human apoA-I concentrations via an increased expression of the human apoA-I gene in liver. Interestingly, liver weight or mRNA levels and activity of fatty acyl-CoA oxidase, a rate-limiting and marker enzyme of peroxisomal ß-oxidation, remain unchanged after fenofibrate.
Conclusions—Expression of the human apoA-I transgene in rabbit liver suffices to confer fibrate-mediated induction of serum apoA-I. Furthermore, these data provide in vivo evidence that the beneficial effects of fibrates on lipoprotein metabolism occur mechanistically dissociated from any deleterious activity on peroxisome proliferation and possibly hepatocarcinogenesis.
Key Words: apolipoproteins • receptors • lipids • drugs • genes
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