In Vivo Actions of Peroxisome Proliferator–Activated Receptors

Peroxisome proliferator–activated receptors (PPARs) form a family of nuclear hormone receptors involved in energy hemostasis and lipid metabolism (1,2) and include three isotypes encoded by different genes: PPARa (chromosome22q12–13.1), PPARb/d (chromosome 6p21.2–21.1), and PPARg (chromosome 3p25). PPARa was the first discovered and causes cellular peroxisome proliferation in rodent livers (3), giving this receptor family its name. Upon activation, PPARs interact with retinoid X receptor to create heterodimers, which bind to a specific DNA sequence motif termed peroxisome proliferator response element (4). Peroxisome proliferator response element usually appears in promoter regions and is constructed from repeats of nucleotide sequence AGGTCA separated by a single nucleotide. PPARa is widely expressed in tissues with high fatty acid catabolic activity: brown fat, heart, liver, kidney, and intestine (5). Upon activation by endogenous fatty acids and their derivatives, PPARa mediates fatty acid catabolism, gluconeogenesis, and ketone body synthesis, mainly in liver (6–9). In rodents, PPARa activation also influences immune modulation (10,11) and amino acidmetabolism (12), reduces plasma triglyceride, reduces muscle and liver steatosis, and ameliorates insulin resistance (IR) (13,14). Pharmacologic PPARa activation is achieved by fibrates (7) and results in reduced (30–50%) triglyceride and VLDL levels by increasing lipid uptake, lipoprotein lipase–mediated lipolysis, and b-oxidation (15). This is accompanied by a modest increase in HDL cholesterol (5–20%), secondary to transcriptional induction of apolipoprotein A-I/A-II synthesis in liver (15). In man, the primary effect of PPARa is to reduce plasma triglyceride concentration; effects on plasma free fatty acid (FFA) concentration/FFA oxidation, muscle/liver fat content, andmuscle/hepatic insulin sensitivity have not been demonstrated with current PPARa agonists such as fenofibrate (16,17). Fibrates are used to treat severe hypertriglyceridemia and combined hyperlipidemia (18–20). Clinical trials to establish a role for PPARa agonists (fenofibrate, gemfibrozil) in primary or secondary cardiovascular prevention in patients with hypertriglyceridemia or diabetes have been disappointing (21,22). Clinically significant effects of fibrates on glucose homeostasis, IR, and insulin secretion in man have not been demonstrated (16,17,23). PPARb/d is expressed ubiquitously, correlating with the level of cellular proliferation exhibited in different tissues (24). In rodents, PPARb/d activation exerts metabolic effects in skin, gut, skeletal muscle, adipose tissue, and brain (25,26). Several PPARb/d agonists are in clinical trials because of their beneficial effects on dyslipidemia (27,28) and other components of metabolic syndrome (29,30). PPARg has two splice variants, PPARg1 and PPARg2, differing by 30 amino acids in the N9 terminal end.While PPARg1 is widely expressed in tissues (skeletal muscle heart, liver) at low levels, both are highly expressed in adipose tissue (31,32). PPARg is considered the “master” regulator of adipogenesis (33). PPARg overexpression in cultured fibroblasts transforms them into adipocytes (34), while selective adipose deletion of PPARg results in lipodystrophy and IR (35–37). Dominant negative PPARg mutations are associated with lipodystrophy (in the limbs and gluteal region), dyslipidemia, hypertension, and severe IR (38– 40). PPARg polymorphisms (specifically, Pro12Ala) are associated with increased risk of developing type 2 diabetes (T2DM) (41–43). PPARg agonists, thiazolidinediones (2,44,45), are potent insulin sensitizers, enhance insulin secretion, improve glucose tolerance, and are the focus of this review.