Review
PPARs and molecular mechanisms of transrepression
Mercedes Ricote
a,
⁎
, Christopher K. Glass
b,
⁎
a
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain
b
Departments of Cellular and Molecular Medicine and Department of Medicine, University of California, San Diego., 9500 Gilman Drive,
La Jolla, CA 92093, USA
Received 8 November 2006; received in revised form 26 February 2007; accepted 27 February 2007
Available online 12 March 2007
Abstract
In the last few years, PPARs have emerged as key regulators of inflammatory and immune responses. However, the mechanistic basis of the
anti-inflammatory effects of peroxisome proliferator-activated receptors (PPARs) remains poorly understood. Accumulating evidence suggests
that these effects result from inhibition of signal-dependent transcription factors that mediate inflammatory programs of gene activation. Several
mechanisms underlying negative regulation of gene expression by PPARs have been described. Recent studies, using siRNA, microarray analysis
and macrophage-specific knockout mice, have highlighted PPARs molecular transrepression mechanism in macrophages. Identification of their
mechanism of action should help promote the understanding of the physiologic roles that PPARs play in immunity and contribute to the
development of new therapeutic agents.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Peroxisome proliferator-activated receptors; Inflammation; Macrophage; Transrepression; Coactivators; Corepressors
1. Introduction
PPARs are members of the nuclear receptor family of ligand-
dependent transcription factors that regulate diverse aspects of
energy homeostasis, lipid and lipoprotein metabolism, and
glucose homeostasis (reviewed in [1,2]). In the last few years,
PPARs have also emerged as key regulators of inflammatory and
immune responses, opening a new area for the development of
therapeutic drugs useful in the treatment of chronic inflamma-
tory diseases such as atherosclerosis, obesity-induced insulin
resistance, and neurodegenerative diseases (reviewed in [3,4]).
There are three PPAR subtypes: α (NR1C1), β/δ (NRC2),
and γ (NRC3), which exhibit distinct tissue distributions
reflecting their biological functions [5,6]. PPARs are activated
by fatty acids and naturally occurring fatty acid-derived mol-
ecules. It has been difficult to definitively establish the exact
molecular species of fatty acids and/or their metabolites that
bind to the various PPARs in vivo. However, considerable
circumstantial evidence suggests that PPARs function as
sensors of a variety of molecules that are derived either from
extracellular or intracellular fatty acid metabolism (exemplified
for PPARγ in Fig. 1). In addition, PPARs can be regulated by
several synthetic compounds. Fibrates, which include clofi-
brate, fenofibrate, bezafibrate, and gemfibrozil are PPARα
ligands widely used clinically to treat hypertriglyceridemia
[7,8]. Thiazolidinediones (TZD), such as rosiglitazone and
pioglitazone, are PPARγ ligands used to treat type 2 diabetes
[9,10].
PPARs activate gene expression by binding to specific DNA
response elements in target genes as heterodimers with the
retinoid X receptors (RXRs) [11,12] (Figs. 1 and 2). This
activity enables PPARs to positively regulate gene networks
involved in the control of lipid metabolism and glucose
homeostasis in several tissues including adipose tissue, muscle
and liver, ultimately influencing circulating lipid and glucose
levels. Because saturated fatty acids have been shown to exert
proinflammatory effects in several cell types [13], effects of
PPAR agonists on circulating levels of these fatty acids could
potentially affect inflammation indirectly. In addition, PPARs
also act directly to negatively regulate gene expression of
Biochimica et Biophysica Acta 1771 (2007) 926 – 935
www.elsevier.com/locate/bbalip
⁎
Corresponding authors. M. Ricote is to be contacted at Tel.: +34 91
4531200; fax: +34 91 4531245. C.K. Glass, Tel.: +1 858 5346011; fax: +1 858
8222127.
E-mail addresses: mricote@cnic.es (M. Ricote), ckg@ucsd.edu
(C.K. Glass).
1388-1981/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbalip.2007.02.013