ReviewMedical significance of peroxisome proliferator-activated receptors
Section snippets
Peroxisomal proliferation
The peroxisome is a subcellular oganelle (figure 1) whose functions extend well beyond the removal of molecular oxygen and later breakdown of hydrogen peroxide, to include glycerolipid synthesis, cholesterol biosynthesis and breakdown (bile-acid formation), and fatty-acid oxidation. Proliferation of peroxisomes induced in rodents is associated with biochemical changes, the most spectacular being the stimulation of peroxisomal fatty acyl-CoA β-oxidation. The multitude of peroxisome proliferation
PPAR structure and function
A PPAR is a compact molecule. Human PPARα has 468 aminoacid residues compared with 441 for PPAR-β/δ and 479 for PPARγ. Like other members of the steroid-receptor superfamily, PPARs have five or six structural regions (A-F) in four functional domains. The C domain is DNA-binding (DBD). The E/F domain is ligand-binding (LBD) and has a key role in the transduction of the hormonal signal into transcriptional activation. Hormone binding to PPARγ modulates an intramolecular communication between the
PPAR and gene expression
PPAR have three isoforms, β, β (or θ), and γ. PPARβ is activated by fatty acids but its role in adipocyte differentiation remains controversial.7 Our emphasis will be on PPARα and PPARγ. The mechanisms by which PPAR are activated and then regulate transcriptional expression of target genes are shown in figure 2. These processes include interaction with a heat-shock protein, cellular signalling that alters the phosphorylation status of PPAR, and the interaction of ligands of both pharmacological
PPAR ligands and their biological significance
Both natural and pharmacological (synthetic) ligands have been described (figure 3). The former may compete with the latter, indicating that they fit similar binding sites. Examples are the natural prostaglandin 15-deoxy-Δ12, 14 -prostaglandin J2 (15d-PGJ2) and the synthetic thiazolidinedione drugs, both of which bind to PPARγ.
PPAR and cellular processes in rodents
PPARα is abundantly expressed in cardiac muscle cells and in organs where gluconeogenesis occurs (liver, intestine, and renal cortex) while PPARγ expression is predominant in white adipose tissue and immune cells. This expression pattern holds for rodents and for man. Disease and drug mediated modulations of one PPAR isoform can thus be expected to alter the function of more than one cell type or tissue. Rodents and man are very different in the way cellular processes are regulated by PPARα (
Inflammatory lipid mediator metabolism
In the mitochondria β-oxidation proceeds to completion but β-oxidation in peroxisomes leads to incomplete shortening of the carbon chain of acyl-CoA. Besides their exclusive contribution to the oxidation of very-long-chain fatty acids (mitochondria cannot deal with fatty acids longer than C22) peroxisomes have a key role in the β-oxidation of bile acids or other metabolites which are not shortened completely such as prostaglandins and leukotrienes. Peroxisomal β-oxidation of fatty acids and
Lack of peroxisome proliferation
The human tissue response to pharmacological PPARα ligands does not include peroxisome proliferation. This explains why adverse effects such as promotion of liver carcinogenesis are not a problem for patients taking fibrates. Human and rodent adaptive responses to inhibition of mitochondrial fatty-acid oxidation or exposure to peroxisome proliferators are very different too. In rodents, the initial insult is counteracted by strong (peroxisomal) and moderate (mitochondrial) induction of
Cellular effects of PPARγ
PPARγ activation promotes cell differentiation in hepatocytes, fibroblasts, myocytes, and breast and colon epithelial cells but it is the role of PPARγ in the adipocyte and monocyte/macrophage that we will focus on here.
PPARs and cardiovascular disorders
The inflammatory activation of aortic smooth-muscle cells, which is a hallmark of atherosclerosis, seems to be inhibited by the enhanced PPARα activity induced by fibrates.29 Activation of PPARα by fibrates leads to the induction of APO-AI24 and APO-AII27 expression in hepatocytes, resulting in an increase in circulating HDL. In rats, however, fibrates suppress APO-AI expression and lower HDL. On the other hand, through stimulation of mitochondrial fatty-acid oxidation, PPARα shifts the human
PPARs and tumour cell growth
Enhanced PPARα expression promoting tumour cell growth has been documented in rodents, especially for hepatocarcinogenesis. As a result, “perixosome proliferators” (eg, fibrates, phthalate ester plasticisers, and pesticides) have been thought of as a new class of nongenotoxic carcinogens This has hampered and in some instances stopped drug development. However, these rodent data are not relevant to man.38 Interspecies variation could include differences in ligand responsiveness of PPAR. Also
Obesity and diabetes
Thiazolidinedione-mediated PPARγ activation leads to stimulation of adipogenesis and to recovery of insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. This paradox-the promotion of adipogenesis in an obesity-linked disease-becomes less troubling when one remembers that obesity is a disorder of energy balance with excess energy stored in fat. Although obesity may be caused by excess food intake (in very rare cases due to mutations in the leptin or leptin receptor
The future, and an update
Therapeutically the ideal-and, therefore, the challenge- is to be able to select a desired PPARγ-mediated endpoint in one cell type without inducing an adverse PPARγ-mediated effect in another. This could mean looking for drugs that can interfere with the different regulatory transcriptional controls of the PPARγ gene or that can interfere directly with the PPARγ proteins. Modification of the phosphorylation state of PPAR affects ligand affinity. PPARγ2 has an additional 28 aminoacids, leading
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