(Circulation. 1998;98:2088-2093.)
© 1998 American Heart Association, Inc.
Cardiovascular Drugs |
Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism
From Unité 325 INSERM (B.S., J.D., J.A., K.S., J.-C.F.), Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France, and Center for Research, Prevention and Treatment of Atherosclerosis (E.L.), Division of Medicine, Hadassah University Hospital, 91120 Jerusalem, Israel.
Correspondence to Jean-Charles Fruchart, Département d'Athérosclérose et INSERM U325, Institut Pasteur de Lille, 1, rue du Prof. Calmette, 59019 Lille Cédex, France. E-mail Jean-Charles.Fruchart{at}pasteur-lille.fr
Abstract
Abstract—Treatment with
fibrates, a widely used class of lipid-modifying agents, results in a
substantial decrease in plasma triglycerides and is usually
associated with a moderate decrease in LDL cholesterol and
an increase in HDL cholesterol concentrations.
Recent investigations indicate that the effects of fibrates are
mediated, at least in part, through alterations in transcription of
genes encoding for proteins that control lipoprotein
metabolism. Fibrates activate specific
transcription factors belonging to the nuclear hormone receptor
superfamily, termed peroxisome proliferator-activated receptors
(PPARs). The PPAR-
form mediates fibrate action on HDL
cholesterol levels via transcriptional induction of
synthesis of the major HDL apolipoproteins, apoA-I and apoA-II.
Fibrates lower hepatic apoC-III production and increase
lipoprotein lipase—mediated lipolysis via PPAR. Fibrates stimulate
cellular fatty acid uptake, conversion to acyl-CoA derivatives, and
catabolism by the ß-oxidation pathways, which, combined with a
reduction in fatty acid and triglyceride synthesis, results
in a decrease in VLDL production. In summary, both enhanced
catabolism of triglyceride-rich particles and reduced
secretion of VLDL underlie the hypotriglyceridemic
effect of fibrates, whereas their effect on HDL metabolism
is associated with changes in HDL apolipoprotein expression.
Key Words: apolipoproteins • arteriosclerosis • fibrates • hypercholesterolemia • hyperlipoproteinemia • lipids • PPAR
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