Elsevier

Pharmacological Research

Volume 60, Issue 3, September 2009, Pages 151-159
Pharmacological Research

Review
The role of PPARα in lipid metabolism and obesity: Focusing on the effects of estrogen on PPARα actions

https://doi.org/10.1016/j.phrs.2009.02.004Get rights and content

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that belongs to the steroid hormone receptor superfamily. PPARα is expressed predominantly in tissues that have a high level of fatty acid catabolism, such as liver, heart, and muscle. PPARα regulates the expression of a number of genes critical for lipid and lipoprotein metabolism. PPARα ligand fibrates have been used for the treatment of dyslipidemia due to their ability to lower plasma triglyceride levels and elevate HDL cholesterol levels. PPARα activators have been shown to regulate obesity in rodents by both increasing hepatic fatty acid oxidation and decreasing the levels of circulating triglycerides responsible for adipose cell hypertrophy and hyperplasia. However, these effects of PPARα on obesity and lipid metabolism may be exerted with sexual dimorphism and seem to be influenced by estrogen. Estrogen inhibits the actions of PPARα on obesity and lipid metabolism through its effects on PPARα-dependent regulation of target genes. Thus, the use of fibrates seems to be effective in men and postmenopausal women with obesity and lipid disorders, but not in premenopausal women with functioning ovaries.

Introduction

Energy homeostasis is maintained by a balance between caloric intake and energy expenditure. The disruption of energy balance due to excessive energy intake is apt to cause a number of metabolic disorders such as dyslipidemia, obesity, type 2 diabetes, atherosclerosis, and hypertension. The peroxisome proliferator-activated receptors (PPARs: PPARα, PPARγ and PPARβ/δ) have been the subject of intense investigation and considerable pharmacological research since they modulate these metabolic risk factors [1], [2], [3]. Thus, modulation of PPAR activity may be an effective therapy for several diseases associated with metabolic syndrome. The PPARα form has been shown to mediate the hypolipidemic effects of fibrates on lipid and lipoprotein metabolism [4], [5]. Moreover, PPARα has been shown to be involved in the regulation of obesity [6], [7]. PPARα activation also mediates improvement of glucose and energy homeostasis, inhibition of vascular inflammation, and correction of age-related dysregulation [8]. This review will focus on the role of PPARα on lipid metabolism and obesity, and the interaction of PPARα with estrogen receptor (ER) in the regulation of obesity and lipid metabolism.

Section snippets

Tissue expression and ligands of PPARα

PPARs are members of the steroid hormone receptor superfamily of ligand-activated transcription factors. These PPARs have the ability to bind chemicals termed peroxisome proliferators that include hypolipidemic fibrates, antidiabetic thiazolidinediones, plasticizers, pesticides, herbicides, and certain fatty acids [9], [10], [11], [12]. There are three PPAR subtypes – PPARα, PPARγ, and PPARβ/δ – with different ligand specificity, very distinct tissue distributions, and different biological

The role of PPARα in lipid metabolism and obesity

Over the last several decades, there have been a number of studies on the physiology, pharmacology, and functional genomics of PPARα. In vivo and in vitro studies demonstrate that PPARα plays a central role in lipid and lipoprotein metabolism, and thereby decreases dyslipidemia associated with metabolic syndrome [31], [54], [55], [56]. Researches have also indicated that PPARα may have antiobesity effects and improve obesity-related disorders [6], [57].

Conclusion

PPARα has been the subject of intense academic and pharmaceutical research because of its ability to perform metabolic and therapeutic actions. Synthetic PPARα activators are widely used as lipid-lowering drugs, which result in a substantial decrease in plasma TGs and an increase in HDL cholesterol, leading to decreased CVD. Fibrates have been shown to be particularly effective at treating dyslipidemic patients with type 2 diabetes or metabolic syndrome. Moreover, PPARα ligands seem to exhibit

Acknowledgements

This study was supported by Korea Research Foundation (grant No. KRF-2006-531-C00052) and Korea Science and Engineering Foundation (grant No. R01-2008-000-20040-0).

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