Peroxisome Proliferator-Activated Receptors (PPARs)

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Abstract

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors. They function as transcription factors and act to regulate gene expression, thus impacting cellular development and diverse metabolic functions including hydrogen peroxide-based respiration, β-oxidation of fatty acids, and cholesterol metabolism. PPAR agonists are known to produce hepatomegaly, hepatic peroxisome proliferation, and hepatocarcinogenicity (rodents only) as well as toxicity in the heart, skeletal muscle, kidney, bone marrow, and lipid tissues (animals and humans). Effects upon the brain (ventricular dilation, hemorrhage) have been seen in dogs and primates administered a PPAR agonist in development. An increased incidence of liver failure caused by the PPAR agonist troglitazone resulted in its removal from the market by the US Food and Drug Administration in 2000.Three types of PPARs have been identified, including α (alpha), β/δ (beta/delta), and γ (gamma). PPARs have a modular structure and consist of an N-terminal region, a region that binds to DNA, a flexible hinge region, a domain that binds to a ligand, and a C-terminal region.PPARs form a heterodimer with the retinoid X receptor, changing their structural conformation. They subsequently bind to the promoter region of the DNA of a target gene. This acts to increase or reduce the gene expression. PPAR functionality is controlled by the shape of its ligand binding domain as well as activator and repressor coproteins (acting to stimulate or inhibit gene expression, respectively). There are several endogenous ligands for PPARs including free fatty acids, eicosanoids, prostaglandin J2, leukotriene B4, as well as agonist drugs.Hereditary dysfunction of PPARs can lead to a loss of their normal function and result in conditions such as lipodystrophy (excess or a deficit of adipose tissue in areas of the body), increased resistance to insulin, obesity, and acanthosis nigricans (brown or black poorly defined hyperpigmentation of the skin often associated with insulin resistant diabetes). A mutation of PPAR γ can also cause a gain of functionality and result in a decrease in resistance to insulin.Fibrate drugs (e.g., clofibrate, removed from the market in 2002 due to cardiotoxicity) were developed to help lower cholesterol and triacylglyceride levels in the blood. Their mechanism of action is via activation of PPAR α. Thiazolidinedione drugs activate PPAR γ and help to control type 2 diabetes. Berberine, a plant alkaloid that activates PPAR γ, is used in Indian and Chinese medications for the treatment of intestinal diarrhea, cholera, and in the eradication of intestinal parasites.This article reviews the various types of PPAR agonists, the mechanism of action PPAR α agonists, the PPAR α-null mouse model used to investigate PPAR α mechanism and summarizes the known toxicities associated with PPAR agonist drugs. International Agency for Research on Cancer and Environmental Protection Agency have recognized that PPAR agonists cause tumors in multiple species, strains, sexes, and at multiple sites in rodents and have classified them as 'probable human carcinogens.'.

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Baran, K. P. (2014). Peroxisome Proliferator-Activated Receptors (PPARs). In Encyclopedia of Toxicology: Third Edition (pp. 812–814). Elsevier. https://doi.org/10.1016/B978-0-12-386454-3.00975-1

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