Ligand-Dependent and -Independent Regulation of PPAR and Orphan Nuclear Receptors

H. Eric Xu^1* and Yong Li^2*

¹ Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Northeast, Grand Rapids, MI 49503, USA.
² Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, 709 Salk Hall, Pittsburgh, PA 15261, USA.

Abstract: Peroxisome proliferator–activated receptor (PPAR) 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 PPAR and two related receptors, PPAR and PPARβ (also known as PPAR), 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 PPAR 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 PPAR, 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.

* Corresponding authors. E-mail, eric.xu{at}vai.org (H.E.X.); yol21{at}pitt.edu (Y.L.)

The editors suggest the following Related Resources on Science sites:

In Science Signaling

RESEARCH ARTICLES
Cell Biology
TIM Family Proteins Promote the Lysosomal Degradation of the Nuclear Receptor NUR77

Savithri Balasubramanian, Satya Keerthi Kota, Vijay K. Kuchroo, Benjamin D. Humphreys, and Terry B. Strom (11 December 2012)
Sci. Signal. 5 (254), ra90. [DOI: 10.1126/scisignal.2003200]
 |  Editor's Summary »  |  Abstract »  |  Full Text »  |  PDF »  |  Supplementary Materials »

EDITORS' CHOICE
Pharmacology
NF-B Needs PPAR

Nancy R. Gough (28 September 2010)
Sci. Signal. 3 (141), ec296. [DOI: 10.1126/scisignal.3141ec296]
 |  Abstract »

EDITORS' CHOICE
Metabolism
A Phosphorylation Target for Diabetes Therapy

Wei Wong (27 July 2010)
Sci. Signal. 3 (132), ec227. [DOI: 10.1126/scisignal.3132ec227]
 |  Abstract »

PERSPECTIVES
Nuclear Receptors
miRNA Regulation Through Ligand Occupancy of a Nuclear Hormone Receptor

Ann E. Rougvie (18 August 2009)
Sci. Signal. 2 (84), pe52. [DOI: 10.1126/scisignal.284pe52]
 |  Abstract »  |  Full Text »  |  PDF »

MEETING REPORTS
Nuclear Receptors
Chemical Approaches to Nuclear Receptors in Metabolism

Ronald N. Margolis, David D. Moore, Timothy M. Willson, and R. Kip Guy (4 August 2009)
Sci. Signal. 2 (82), mr5. [DOI: 10.1126/scisignal.282mr5]
 |  Abstract »  |  Full Text »  |  PDF »

PERSPECTIVES
Structural Biology
Allosteric Effects Govern Nuclear Receptor Action: DNA Appears as a Player

Hinrich Gronemeyer and William Bourguet (2 June 2009)
Sci. Signal. 2 (73), pe34. [DOI: 10.1126/scisignal.273pe34]
 |  Abstract »  |  Full Text »  |  PDF »

EDITORS' CHOICE
Nuclear Receptors
Translating Hormone Cues Tissue-Specifically

Annalisa M. VanHook (7 April 2009)
Sci. Signal. 2 (65), ec120. [DOI: 10.1126/scisignal.265ec120]
 |  Abstract »

PERSPECTIVES
Nuclear Receptors
Von Gierke’s Disease Adopts an Orphan (and Its Partner)

Alan Cheng and Alan R. Saltiel (17 February 2009)
Sci. Signal. 2 (58), pe8. [DOI: 10.1126/scisignal.258pe8]
 |  Abstract »  |  Full Text »  |  PDF »

EDITORS' CHOICE
Nuclear Receptors
Ligand Not Required?

Nancy R. Gough (9 September 2008)
Sci. Signal. 1 (36), ec316. [DOI: 10.1126/scisignal.135ec316]
 |  Abstract »

EDITORS' CHOICE
NUCLEAR RECEPTORS
Receptors Without Ligands

(3 June 2003)
Sci. STKE 2003 (185), tw208. [DOI: 10.1126/scisignal.1852003tw208]
 |  Abstract »