Peroxisome proliferator-activated receptors: Lipid binding proteins controling gene expression

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. Since their discovery in the beginning of the nineties the three isoforms ( PPARalpha, beta/delta and gamma, encoded by different genes) have been implicated in the regulation of almost every single aspect of lipid metabolism and, consequently, in diseases that involve disturbances in lipid metabolism ( obesity, diabetes, atherosclerosis, cardiac failure). Although their prominent role in these processes has hardly been disputed, the way in which the activity of these transcription factors is regulated under physiological and pathological conditions awaits further clarification. An unresolved issue has been the nature of the natural ligand of these receptors. Biochemical studies have shown that the PPAR isoforms are rather promiscuous with respect to ligand binding, with a large variety of naturally occurring lipid-like substances acting as low-affinity ligands. More recently this concept has been confirmed by crystallographic studies on the ligand-binding pocket. In addition to ligand availability, the trans-activating capacity likely depends on phosphorylation status of the PPARs and on the recruitment of auxiliary proteins (co-activators and corepressors). Accordingly, the biological activity of these key-regulators of metabolism is controlled at multiple levels, which enables each tissue to fine tune its metabolic machinery to the demands of the body in a specific fashion.