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Journal of Lipid Research, Vol 37, 907-925, Copyright © 1996 by Lipid Research, Inc.
K Schoonjans, B Staels and J Auwerx
The three types of peroxisome proliferator-activated receptors (PPAR),
termed alpha, delta (or beta), and gamma, belong to the nuclear receptor
superfamily. Although peroxisome proliferators, including fibrates and
fatty acids, activate the transcriptional activity of these receptors, only
prostaglandin J2 derivatives have been identified as natural ligands of the
PPAR gamma subtype that also binds thiazolidinedione antidiabetic agents
with high affinity. PPARs heterodimerize with retinoic X receptor (RXR) and
alter the transcription of target genes after binding to response elements
or PPREs, consisting of a direct repeat of the nuclear receptor hexameric
DNA recognition motif (PuGGTCA) spaced by 1 nucleotide (DR-1). Upon
activation by fatty acids (FAs) and drugs that affect lipid metabolism,
PPARs control the expression of genes implicated in intra- and
extracellular lipid metabolism, most notably those involved in peroxisomal
beta-oxidation. PPARs partially mediate the inductive effects of fibrates
and fatty acids on high density lipoprotein (HDL) cholesterol levels by
regulating the transcription of the major HDL apolipoproteins, apoA-I and
apoA-II. The hypotriglyceridemic action of fibrates and certain fatty acids
also involves PPAR and is constituted of: 1) increased hydrolysis of plasma
triglycerides due to induction of LPL and reduction of apoC-III expression;
2) stimulation of cellular fatty acid uptake and conversion to acyl-CoA
derivatives due to increased expression of genes for fatty acid transport
protein and acyl- CoA synthetase; 3) increased peroxisomal and
mitochondrial beta- oxidation; and 4) decreased synthesis of fatty acids
and triglycerides and decreased production of very low density lipoprotein
(VLDL). Hence, both enhanced catabolism of triglyceride-rich particles and
reduced secretion of VLDL particles contribute to the hypolipidemic effect
of fibrates and fatty acids. Finally, PPARs appear to be involved in
differentiation processes because activation of PPAR gamma 2 triggers
adipocyte differentiation and stimulates expression of several genes
critical to adipogenesis. It is suggested that PPARs are key messengers
responsible for the translation of nutritional and pharmacological stimuli
into changes in gene expression and differentiation pathways.
REVIEWS
Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression
U.325 INSERM, Department d'Atherosclerose, Institut Pasteur de Lille, France.
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