Elsevier

The Lancet

Volume 354, Issue 9173, 10 July 1999, Pages 141-148
The Lancet

Review
Medical significance of peroxisome proliferator-activated receptors

https://doi.org/10.1016/S0140-6736(98)10364-1Get rights and content

Summary

Peroxisome proliferator-activated receptors (PPAR) were discovered in 1990, ending 25 years of uncertainty about the molecular mechanisms of peroxisome proliferation. Subsequently, PPARs have improved our understanding of adipocyte differentiation. But there is more to PPARs than solving a puzzle about an organelle (the peroxisome) long considered an oddity, and their medical significance goes beyond obesity too. Enhanced PPAR type α expression protects against cardiovascular disorders though the role of enhanced PPARγ expression seems less favourable. PPAR mechanisms, mainly via induction of more differentiated cell phenotypes, protect against some cancers. The differentiation of many cell types (hepatocyte, fibroblast, adipocyte, keratinocyte, myocyte, and monocyte/macrophage) involves PPARs, and these nuclear receptors are now attracting the attention of many medical specialties and the pharmaceutical industry.

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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