TY - JOUR
T1 - Peroxisome proliferator-activated receptors
T2 - From genes to physiology
AU - Kliewer, Steven A.
AU - Xu, H. Eric
AU - Lambert, Millard H.
AU - Willson, Timothy M.
PY - 2001
Y1 - 2001
N2 - The peroxisome proliferator-activated receptors (PPARα, γ, δ) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARα (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARα agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARγ (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARα and PPARα, relatively little is known about the biology of PPARδ (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
AB - The peroxisome proliferator-activated receptors (PPARα, γ, δ) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARα (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARα agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARγ (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARα and PPARα, relatively little is known about the biology of PPARδ (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
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U2 - 10.1210/rp.56.1.239
DO - 10.1210/rp.56.1.239
M3 - Review article
C2 - 11237216
AN - SCOPUS:0035786906
SN - 0079-9963
VL - 56
SP - 239
EP - 263
JO - Recent progress in hormone research
JF - Recent progress in hormone research
ER -