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Ligand-Dependent and -Independent Regulation of PPAR{gamma} and Orphan Nuclear Receptors

Peroxisome proliferator–activated receptor γ (PPARγ) is considered to be a ligand-activated nuclear receptor with essential roles in adipogenesis, glucose and lipid homeostasis, and inflammatory responses. An unusually large ligand-binding pocket is a distinguishing feature of PPARγ and two related receptors, PPARα and PPARβ (also known as PPARδ), which allows these receptors to interact with diverse chemical ligands including various fatty acids, fibrates, and the thiazolidinedione class of antidiabetic drugs. However, the physiologically relevant ligand of PPARs remains unknown. A PPARγ mutant that is incapable of binding ligands unexpectedly directed adipogenesis when introduced into fibroblasts. This raises key issues regarding the existence and roles of the hypothetical physiological ligands for PPARγ, issues that may also apply to other “orphan” nuclear receptors lacking bona fide ligands. Identification of the physiological ligands of PPARs and orphan nuclear receptors will be crucial for understanding the biology of these receptors.

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