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Dr. J.A. Illingworth
PPARs are an important class of nuclear proteins involved in diabetes, obesity, inflammation, atherosclerosis, cancer, wound healing and the design of new drugs.
Peroxisome proliferators (PPs) are small molecules that increase hepatic peroxisomes. PPs include plasticisers, herbicides, unsaturated lipids, eicosanoids [prostaglandin family], fibrates [plasma lipid lowering drugs] and thiazolidinediones [insulin sensitising agents]. Some of these xenobiotics cause hepatomegaly and liver cancers in rats, but there is less risk of cancer in humans. PPs bind to peroxisome proliferator activated receptors (PPARs) which are nuclear proteins that modify gene expression.
All PPARs are transcription factors from the nuclear hormone receptor family that form heterodimers with retinoid X receptors (which bind 9-cis-retinoic acid). The heterodimers can bind to numerous AGGTCA-AGGTCA direct repeat peroxisome proliferator response elements (PPREs) scattered throughout the genome, modulating the expression of adjacent genes. mRNA transcription responds both to PPAR ligands and to retinoid X receptor ligands.
All PPARs have a similar structure: N-terminal A/B region with AF1 ligand independent transactivation domain, C region with twin zinc finger DNA binding domain, D, E and F regions with a large and flexible ligand binding site, and AF2 ligand-dependent transactivation domain at the extreme C terminus.
PPAR a (468 amino acids, chromosome 22q13.3) activates many lipid oxidation genes in the peroxisomal, mitochondrial and cytochrome p450 pathways. It also promotes gluconeogenesis, represses genes for amino acid catabolism and has anti-inflammatory actions. PPAR a is expressed mainly in brown fat and liver, followed by heart, kidney and gut. It is the target for fibrate drugs, such as gemfibrozil.
PPAR g (475 / 505 amino acids, chromosome 3p25.1) is necessary and sufficient for adipocyte differentiation, both brown fat and white fat, and produces small, metabolically active cells derived from the fibroblast lineage. It is expressed mainly in adipocytes and in the foam cells of atherosclerotic lesions. It is also needed for heart and placental development. It is the target for thiazolidinedione drugs, such as rosiglitazone.
PPAR g agonists increase insulin sensitivity, "normalise" serum lipids and suppress the synthesis of leptin, resistin and TNF a by fat cells (but probably not by macrophages).
PPAR d (alias PPAR b; 441 amino acids, chromosome 6p21.2) is expressed in many tissues, including brain. It is involved in reverse cholesterol transport and is claimed to be a negative regulator of PPAR a and PPAR g although the evidence is weak. PPAR d controls the apoptotic response to pro-inflammatory cytokines such as TNF a. PPAR d and PPAR a are involved in epidermal differentiation and wound repair.
It is possible to prepare PPAR a (-/-) and PPAR d (-/-) knockout mice, but PPAR g (-/-) mutants are not viable because of placental and heart defects. Unexpectedly, PPAR g (+/-) heterozygotes, which express 50% of normal PPAR g show increased insulin sensitivity, with normal body weight and fat stores.
In addition to binding PPARs and modulating downstream gene expression, some PPs also control the expression of the PPAR genes themselves. For example, the insulin-sensitiser troglitazone (currently withdrawn) reduces the expression of PPAR g while stimulating that of PPAR a in mononuclear cells in obese subjects. Increased PPAR g expression in foam cells probably reflects the inducing effects of oxidised LDL.
Phosphorylation by MAP kinase activates PPAR a but inhibits PPAR g.
Mammalian cells contain numerous PPAR coactivators including CBP, PBP, PGC1, PRIP, p300 and SRC1. These coactivators bind to PPARs and to other nuclear receptors in an agonist-dependent combinatorial manner using an LXXLL motif. [CBP is CREB binding protein, PBP is PPAR binding protein (= TRAP220 or thyroid hormone receptor-associated protein), PGC1 is PPAR g coactivator 1, PRIP is PPAR interacting protein, p300 is adenovirus E1A binding protein and SRC1 is steroid receptor coactivator 1. PGC2 is another type of PPAR coactivator that lacks an LXXLL motif.]
PGC-1 (alias PGC1, PPARGC1) is a transcription coactivator for PPAR a and PPAR g which increases expression of uncoupling protein UCP1 driven by thyroid hormone and PPAR g in brown fat, white fat and skeletal muscle. PGC1 also activates GLUT4 transcription in cultured muscle cells.
The PGC-1 gene contains a full-length palindromic cyclic AMP response element and gene expression is strongly activated by cAMP and CREB [cAMP response element binding protein.] PGC-1 increases transcription of the key gluconeogenic enzymes such as PEPCK in liver.
Cytokines such as IL-1 and TNF a activate PGC-1 via p38 MAP kinase, contributing to the sustained rise in temperature associated with the cachexic state.
PGC1 drives the expression of "mitochondrial" genes and associated proteins such as myoglobin when artificially expressed in white muscle type 2B fibres, artificially converting them into oxidative type 1 fibres. Mitochondrial gene expression involves the participation of NRF1 [nuclear respiratory factor 1].
Some recent reviews on PPARs that are available electronically in Leeds:
Berger & Moller (2002) Annu. Rev. Med. 53, 409-435. The mechanisms of action of PPARs.
Crowley et al (2002) Nature Reviews Drug Discovery 1(4), 276-286. Obesity therapy: Altering the energy intake and expenditure balance sheet.
Kersten (2002) Eur J Pharmacol 440(2-3), 223-234. Peroxisome proliferator activated receptors and obesity.
OMIM [On-line Mendelian Inheritance in Man]
Picard & Auwerx (2002) Annu. Rev. Nutr. 22, 167-197. PPAR g and glucose homeostasis.
Wahli (2002) Swiss Med Wkly 132(7-8), 83-91. Peroxisome proliferator-activated Receptors (PPARs): from metabolic control to epidermal wound healing.
Dr. J.A. Illingworth email: firstname.lastname@example.org Room 8.20e Garstang Building Ext. 33135