PPARG:RXRA heterodimer binds to fatty acid-like ligands

Stable Identifier
R-HSA-381309
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

PPARG can be activated in cell cultures by adding ligands such as polyunsaturated fatty acids and certain prostanoids (prostaglandins). Endogenous fatty acids are relatively poor activators. Which ligands are most responsible for PPARG activation in the body has not yet been established. Generally, oxidized fatty acids such as 9(S')-hydroxyoctadeca-10,12-dienoic acid (9(S')-HODE) and 13(S')-HODE are more effective activators than are endogenous fatty acids. The thiazolidinedione (TZD) class of antidiabetic drugs are agonist ligands for PPARG (Lambe and Tugwood 1996).
FABP4 delivers ligands to PPARG directly. Binding of activator ligands to PPARG causes loss of corepressors such as SMRT/NCoR2, NCoR1, and HDAC3 and gain of interactions with the basal transcription machinery (Yoo et al. 2006). The TRAP220/MED1/DRIP205 subunit of the TRAP/Mediator (DRIP) complex binds directly to the LXXLL motif of PPARG and TRAP/Mediator is necessary for full transcriptional activation of target genes (Ge et al. 2008). PPARG also interacts with the MED14 subunit of the Mediator complex (Grontved et al. 2010).
Other coactivators, including NCOA1/SRC-1, NCOA2/TIF2/GRIP1, CBP, HAT/p300, and PRIP, interact with PPARG in a ligand-dependent way and enhance transcription (Gellman et al. 1999, Wallberg et al. 2003, Yang et al. 2000, Ge et al. 2002, Puigserver et al. 1999, Bugge et al. 2009, Steger et al. 2010).
The target genes of PPARG encode proteins involved in adipocyte differentiation (PGAR/ANGPTL4, PLIN, and aP2/FABP4), carbohydrate metabolism (PEPCK-C), and fatty acid transport (FAT/CD36, LPL).

Literature References
PubMed ID Title Journal Year
19172745 Structural basis for the activation of PPARgamma by oxidized fatty acids

Itoh, T, Fairall, L, Amin, K, Inaba, Y, Szanto, A, Balint, BL, Nagy, L, Yamamoto, K, Schwabe, JW

Nat. Struct. Mol. Biol. 2008
17011499 Transcriptional control of adipocyte formation

Farmer, SR

Cell Metab 2006
8706692 A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs

Lambe, KG, Tugwood, JD

Eur J Biochem 1996
8970730 Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology

Lemberger, T, Desvergne, B, Wahli, W

Annu Rev Cell Dev Biol 1996
10075656 p300 interacts with the N- and C-terminal part of PPARgamma2 in a ligand-independent and -dependent manner, respectively

Gelman, L, Zhou, G, Fajas, L, Raspé, E, Fruchart, JC, Auwerx, J

J Biol Chem 1999
9065481 Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists

Mukherjee, R, Jow, L, Croston, GE, Paterniti JR, Jr

J Biol Chem 1997
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