PPARα:: its role in the human metabolic syndrome

The metabolic syndrome, also known as 'syndrome X' or 'insulin-resistance syndrome', has emerged as a constellation of risk factors that markedly increase the risk of Type 2 diabetes and cardiovascular disease (CVD). The metabolic syndrome is characterized by central obesity, elevated blood pressure, insulin resistance, impaired glucose tolerance or diabetes mellitus and atherogenic dyslipidemia. Nonalcoholic fatty liver disease is strongly associated with the metabolic syndrome and recently both a proinflammatory state and a prothrombotic state have been added as independent components of this syndrome. Since the prevalence of diabetes and obesity is rising at an alarming rate, the incidence of this morbid syndrome is also expected to continue to grow, both in the USA and worldwide, and will likely impact heavily on the incidence of CVD, the leading cause of morbidity and mortality around the world. Peroxisome proliferator-activated receptor (PPAR)CC is a member of the nuclear receptor superfamily, that includes other PPAR isoforms (PPPAR beta/delta and PFAR gamma) and the estrogen, androgen and glucocorticoid receptors. PPAR alpha is a master transcription factor that regulates genes involved in lipid metabolism, glucose homeostasis, inflammation and atherosclerosis, and is the principal regulator of energy homeostasis. Fibrates are hypolipidemic drugs that are weak ligands for PPARa. The lipid (triglyceride)lowering actions of this class of drugs are mediated by modulation of lipid metabolism through molecular actions of PPAR alpha. Fibrates and other PPAR alpha ligands also exert antiinflammatory and anti-thrombotic actions in the constituent cells of the vessel wall. Thus, PPAR alpha agonists interfere with the progression of atherosclerosis by modulating the function of various components of the metabolic syndrome and through their anti-inflammatory properties. Several clinical trial studies with fibrates further confirmed that these drugs have a significant protective effect against CVD. This article focuses on the current understanding of the critical role of PPARa in regulating fatty-acid p-oxidation, lipoprotein metabolism, insulin secretion and sensitivity, vascular inflammation and the cardiovascular system. Furthermore, an overview of the metabolic syndrome, its historical perspective and recent developments about the functional relevance of PPARa to the pathophysiology of the metabolic syndrome are reviewed.