Reactome | Fatty acid ligands activate PPARA

Fatty acid ligands activate PPARA

Stable Identifier

R-HSA-400143

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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PPAR-alpha is activated by binding polyunsaturated fatty acids especially those having 18-22 carbon groups and 2-6 double bonds such as linoleiate, linolenate, arachidonate, and eicosapentaenoate. These ligands bind the C-terminal region of PPAR-alpha. The fibrate drugs are also agonists of PPAR-alpha.
Binding of a ligand causes a conformational change in PPAR-alpha so that it recruits coactivators. By analogy with the closely related receptor PPAR-gamma, PPAR-alpha probably binds TBL1 and TBLR1, which are responsible for recruiting the 19S proteasome to degrade corepressors during the exchange of corepressors for coactivators. The coactivators belong to the CBP-SRC-HAT complex (CBP/p300, SRC1, SRC2, SRC3, CARM1, SWI/SNF, BAF60C, PRIC320, and PRIC285), the ASC complex (PRIP/ASC2, PIMT), and the TRAP-DRIP-ARC-MEDIATOR complex (TRAP130, PBP/TRAP220). The coactivators contain LXXLL motifs (Nuclear Receptor Boxes) that interact with the AF-2 region in nuclear receptors such as PPAR-alpha. Additionally bilirubin binds to PPAR-alpha and acts as coactivator.

Literature References

PubMed ID	Title	Journal	Year
19289416	L-FABP directly interacts with PPARalpha in cultured primary hepatocytes Hostetler, HA, McIntosh, AL, Atshaves, BP, Storey, SM, Payne, HR, Kier, AB, Schroeder, F	J Lipid Res	2009
17306620	Transcription coactivators for peroxisome proliferator-activated receptors Yu, S, Reddy, JK	Biochim Biophys Acta	2007
18288277	Peroxisome proliferator activated receptors and lipoprotein metabolism Kersten, S	PPAR Res	2008
11330046	Peroxisome proliferator-activated receptors, coactivators, and downstream targets Qi, C, Zhu, Y, Reddy, JK	Cell Biochem Biophys	2000
14980219	A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors Perissi, V, Aggarwal, A, Glass, CK, Rose, DW, Rosenfeld, MG	Cell	2004
11226238	Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus Wolfrum, C, Borrmann, CM, Borchers, T, Spener, F	Proc Natl Acad Sci U S A	2001
10529898	Peroxisome proliferator-activated receptors: nuclear control of metabolism Desvergne, B, Wahli, W	Endocr Rev	1999
9171241	Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay Krey, G, Braissant, O, L'Horset, F, Kalkhoven, E, Perroud, M, Parker, MG, Wahli, W	Mol Endocrinol	1997
17007889	Selectivity of fatty acid ligands for PPARalpha which correlates both with binding to cis-element and DNA binding-independent transactivity in Caco-2 cells Mochizuki, K, Suruga, K, Fukami, H, Kiso, Y, Takase, S, Goda, T	Life Sci	2006
16476485	From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions Feige, JN, Gelman, L, Michalik, L, Desvergne, B, Wahli, W	Prog Lipid Res	2006
27071062	Bilirubin Binding to PPARα Inhibits Lipid Accumulation Stec, DE, John, K, Trabbic, CJ, Luniwal, A, Hankins, MW, Baum, J, Hinds, TD	PLoS One	2016
16503871	Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis Gouni-Berthold, I, Krone, W	Curr Drug Targets Cardiovasc Haematol Disord	2005