Role of PPAR in the Pharmacological Regulation of Lipoprotein Metabolism by Fibrates and Thiazolidinediones

Abstract

Abstract: The peroxisome proliferator activated receptors or PPARs constitute a subfamily of the nuclear hormone receptor superfamily of transcription factors. PPARs form heterodimeric complexes with the 9-cis retinoic acid receptor (RXR), which bind to specific response elements, termed peroxisome proliferator response element (PPRE), located in the regulatory regions of target genes. As such they modulate the transcri­ ptional activity of genes, the majority of which are involved in lipid and lipoprotein metabolism. To date three PPAR variants, a, (◊) and y, have been identified, each displaying a specific tissue distribution pattern. Although the function of the PPARO variant remains unknown, evidence coming from different rodent model systems indicates that the PPARa plays a crucial role in hepatic lipid metabolism, whereas PPARy participates in adipocyte differentiation and function. Although only for PPARy natural (prostaglandin J2) and synthetic (the thiazolidinedione BRL 49653) ligands have been identified sofar, all PPARs are activated by a wide variety of chemicals amongst which the hypolipidemic drugs fibrates and the antidiabetic thiazolidinediones. Evidence is now accumulating that the hypotriglyceridemic action of fibrates in humans is primarily mediated via activation of PPARa in liver resulting in the repression of the expression of apo C-III, a key-player in plasma triglyceride metabolism. In addition the high density lipoprotein (HDL)-raising activity of fibrates is linked to a PPARa- mediated induction of the major HDL apolipoproteins, apo A-I and apo A-II in liver. By contrast, whereas the link between PPARy activation and glucose metabolism is still unclear, the antidiabetic thiazolidinediones exert a potent hypotriglyceridemic action via the induction of lipoprotein lipase (LPL) expression in adipose tissue. Due to the involvement of different PPAR variants, fibrates and thiazolidinediones act through distinct and complementary mechanisms on plasma triglyceride metabolism. The identification of the molecular mechanism of action of these pharmacological agents, and the role distinct transcription factors of the PPAR family play therein, suggests that compounds activating both PPARa and PPARy should be very potent hypotriglyceridemic drugs, which may be of use in the treatment of the dyslipidemia associated with atherosclerosis and non-insulin dependent diabetes mellitus.