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In humans the fibrates are useful in the treatment of dyslipidemia by lowering serum triglycerides and raising HDL cholesterol (HDLc). They function by increasing clearance and decreasing the synthesis of very low density lipoproteins (VLDL) which are rich in triglycerides (10). Fibrates also lower serum levels of apolipoprotein Clll (apoCIII) which is a known inhibitor of VLDL clearance. PPARa is also implicated in atherosclerosis. Agonists have been shown to down-regulate the expression ofVCAM-1, inhibition of NF-kB, inhibition of AP-1, and the reduction of plasma levels of interleukin-6, fibrinogen and C-reactive protein (11-14).

PPARy has a surprisingly high degree of homology (95%) across all the species in which it has been cloned (15). Two isoforms of PPARy have been detected in humans. Even though the isoforms have different tissue distributions, their functional differences are still unclear (16-18). PPARy is central in the regulation of adipocyte differentiation (19, 20). This differentiation in turn leads to the expression of several other genes involved in glucose and lipid homeostasis (see ref 1 and references therein). The natural ligands for PPARy known to date, eicosanoids and their metabolites such as prostaglandin J2, are weak agonists with EC50S in the micromolar range. PPARy is an important regulator of target genes involved in glucose and lipid metabolism (21). The key finding that the thiazolidinedione (TZD) antidiabetic drugs Avandia (rosiglitazone, 4) and Actos (pioglitazone, 5) were PPARy agonists led to an explosion of research in the area (22, 23).

The finding that PPARy is expressed in macrophage foam cells has stimulated research in the potential use of PPARy ligands as anti atherogenic agents since foam cells are precursors to atherosclerotic lesions (24-26).

PPAR8 was cloned from a number of species in the early 1990's (1). It has been known by several names such as NUC1 (27), FAAR (28) and PPAR0 (29) but the generally accepted name today is PPAR5 (27-29). The LBDs of the human and rodent receptors are about 90% homologous. The fact that PPAR5 is ubiquitously expressed, and that there are few potent selective ligands available, has hampered research in determining its biological function (30,31). Unlike PPARa and PPARy no drugs have been identified that target PPAR8. Recently, there have been hints that PPAR5 agonist may be useful for treating dyslipidemia and certain dermatological conditions while an antagonist may be useful for osteoporosis and for colorectal cancer (32-35). PPAR8 binds various long chain fatty acids at micromolar concentration making it a likely fatty acid sensor (36). Recently this interaction with fatty acids has been linked to VLDL particles which can activate PPAR8 in macrophages, potentially implicating this nuclear receptor in atherosclerosis (37).

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