PPAR

From LipidomicsWiki

The peroxisome proliferator-activated receptors (PPAR , , ) are activated by polyunsaturated fatty acids, eicosanoids, and various synthetic ligands (Willson and Brown 2000). Consistent with their distinct expression patterns, gene-knockout experiments have revealed that each PPAR subtype performs a specific function in fatty acid homeostasis.

Over a decade ago, PPAR was found to respond to hypolipidemic drugs, such as fibrates. Subsequently, it was discovered that fatty acids serve as their natural ligands. Together with the analyses of PPAR null mice, these studies established PPAR as a global regulator of fatty acid catabolism. PPAR target genes function together to coordinate the complex metabolic changes necessary to conserve energy during fasting and feeding. In the fatty acid metabolic cascade, PPAR activation up-regulates the transcription of liver fatty acid-binding protein, which buffers intracellular fatty acids and delivers PPAR ligands to the nucleus(Wolfrum et al. 2001). In addition, expression of two members of the adrenoleukodystrophy subfamily of ABC transporters, ABCD2 and ABCD3, is similarly up-regulated to promote transport of Fatty acids into peroxisomes (Fourcade et al. 2001) where catabolic enzymes promote -oxidation. The hepatocyte CYP4A enzymes complete the metabolic cascade by catalyzing -oxidation, the final catabolic step in the clearance of PPAR ligands (Lee et al. 1995).

PPAR was identified initially as a key regulator of adipogenesis, but it also plays an important role in cellular differentiation, insulin sensitization, atherosclerosis, and cancer (Rosen and Spiegelman 2001). Ligands for PPAR include fatty acids and other arachidonic acid metabolites, antidiabetic drugs (e.g., thiazolidinediones), and triterpenoids. In contrast to PPAR , PPAR promotes fat storage by increasing adipocyte differentiation and transcription of a number of important lipogenic proteins. Ligand homeostasis is regulated by governing expression of the adipocyte fatty acid-binding protein (A-FABP/aP2) and CYP4B1 (Way et al. 2001). In macrophages, PPAR induces the lipid transporter ABCA1 through an indirect mechanism involving the LXR pathway (see below), which in turn promotes cellular efflux of phospholipids and cholesterol into high-density lipoproteins (Chawla et al. 2001; Chinetti et al. 2001).

Despite our understanding of the roles of PPAR and , knowledge of the function of PPAR has emerged more slowly (Wollson and Brown 2000). Ligands for PPAR include long-chain fatty acids and carboprostacyclin. The recent identification and study of synthetic, high-affinity PPAR ligands also suggest a role for this receptor in lipid metabolism (Oliver et al. 2001; Vosper et al. 2001).

Pharmacological activation of PPAR in macrophages and fibroblasts results in up-regulation of the ABCA1 transporter, and because of its widespread expression, PPAR may affect lipid metabolism in peripheral tissues (Oliver et al. 2001; Vosper et al. 2001). Consistent with this notion, PPAR -null mice are growth retarded and have reduced adipocyte mass and myelination in their central nervous system (Peters et al. 2000; Barak et al.).