Pleiotropic Actions of Peroxisome Proliferator–Activated Receptors in Lipid Metabolism and Atherosclerosis

Abstract

Abstract-Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPAR␣ mediates the hypolipidemic action of fibrates, PPAR␥ is the receptor for the antidiabetic glitazones. PPAR␣ is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the ␤-oxidative degradation of fatty acids. PPAR␥ is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPAR␤/␦ is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPAR␣ controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPAR␣ and PPAR␥ regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall. Key Words: nuclear receptors Ⅲ HDL Ⅲ inflammation Ⅲ cholesterol Ⅲ atherosclerosis T he metabolic syndrome, which can be defined as the clustering of cardiovascular risk factors with insulin resistance, is characterized by the simultaneous presence of one or more of the following metabolic disorders: glucose intolerance, hyperinsulinemia, dyslipidemia, coagulation disturbances, and hypertension. Peroxisome proliferator-activated receptors (PPARs) modulate these metabolic risk factors for cardiovascular disease associated with the metabolic syndrome. Whereas previous articles have summarized our present understanding of the role of PPARs in the control of glucose homeostasis, insulin resistance, and hypertension (see reviews 1,2 ), the present review will focus on the plasma lipid-controlling actions of PPARs and their effects on atherogenesis. Levels of Control of PPAR ActivityFatty acids (FAs) and FA-derived compounds are natural ligands for PPAR␣ and PPAR␥. Natural eicosanoids derived from arachidonic acid via the lipoxygenase pathway, such as 8-S-hydroxytetraenoic acid and leukotriene B4, and oxidized phospholipids from oxidized lipoproteins activate PPAR␣. 3 PPAR␥ is a receptor for eicosanoid metabolites formed via the cyclooxygenase pathway, eg, prostaglandins, such as PGJ 2 , PGH 1 , and PGH 2 , 4 and via the lipoxygenase pathway (15-hydroxytetraenoic acid). 3 Simila...

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

“…Furthermore, some studies have suggested that PPARα has a direct antiatherogenic action, regulating the expression of key proteins involved in all stages of atherogenesis, including vascular inflammation [19].…”

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

“…In particular, nuclear receptors are associated with the regulation of metabolic homeostasis, through both the action of endosensing receptors such as LXR, FXR and PPAR (Barbier et al, 2002;Mohan and Heyman, 2003), and xenosensing receptors such as PXR and CAR (Bachmann et al, 2004;Pascussi et al, 2008;Wada et al, 2009). Thus, exposure to noncoplanar PCBs may lead to chronic activation of PXR/CAR and potential dysfunction of these metabolic processes.…”

Effects of telmisartan and losartan on cardiovascular protection in Japanese hypertensive patients

“…11 MetS is also known to be associated with disorders of peroxisome proliferatoractivated receptor-g (PPARg), 12 an intracellular hormone receptor with a significant role in carbohydrate and lipid metabolism. 13 PPARg agonists improve insulin resistance in patients with type 2 diabetes mellitus (DM). 14,15 Telmisartan bears a structural resemblance to PPARg agonist pioglitazone, which suggests that telmisartan may activate PPARg.…”