Endogenous bile acids are ligands for the nuclear receptor FXR/BAR - PubMed (original) (raw)
Endogenous bile acids are ligands for the nuclear receptor FXR/BAR
H Wang et al. Mol Cell. 1999 May.
Free article
Abstract
The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
Similar articles
- Bile acids: natural ligands for an orphan nuclear receptor.
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. Parks DJ, et al. Science. 1999 May 21;284(5418):1365-8. doi: 10.1126/science.284.5418.1365. Science. 1999. PMID: 10334993 - Identification of a nuclear receptor for bile acids.
Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Makishima M, et al. Science. 1999 May 21;284(5418):1362-5. doi: 10.1126/science.284.5418.1362. Science. 1999. PMID: 10334992 - Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor.
Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Pineda Torra I, et al. Mol Endocrinol. 2003 Feb;17(2):259-72. doi: 10.1210/me.2002-0120. Mol Endocrinol. 2003. PMID: 12554753 - FXR, a bile acid receptor and biological sensor.
Tu H, Okamoto AY, Shan B. Tu H, et al. Trends Cardiovasc Med. 2000 Jan;10(1):30-5. doi: 10.1016/s1050-1738(00)00043-8. Trends Cardiovasc Med. 2000. PMID: 11150726 Review.
Cited by
- GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression.
Zhang S, Pan X, Jeong H. Zhang S, et al. Drug Metab Dispos. 2015 May;43(5):743-8. doi: 10.1124/dmd.114.062836. Epub 2015 Feb 27. Drug Metab Dispos. 2015. PMID: 25725071 Free PMC article. - Increased Bile Acid Synthesis and Deconjugation After Biliopancreatic Diversion.
Ferrannini E, Camastra S, Astiarraga B, Nannipieri M, Castro-Perez J, Xie D, Wang L, Chakravarthy M, Haeusler RA. Ferrannini E, et al. Diabetes. 2015 Oct;64(10):3377-85. doi: 10.2337/db15-0214. Epub 2015 May 26. Diabetes. 2015. PMID: 26015549 Free PMC article. - Intestinal synthesis and secretion of bile salts as an adaptation to developmental biliary atresia in the sea lamprey.
Yeh CY, Chung-Davidson YW, Wang H, Li K, Li W. Yeh CY, et al. Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11419-24. doi: 10.1073/pnas.1203008109. Epub 2012 Jun 25. Proc Natl Acad Sci U S A. 2012. PMID: 22733776 Free PMC article. - Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.
Soroka CJ, Boyer JL. Soroka CJ, et al. Mol Aspects Med. 2014 Jun;37:3-14. doi: 10.1016/j.mam.2013.05.001. Epub 2013 May 15. Mol Aspects Med. 2014. PMID: 23685087 Free PMC article. Review. - Non-alcoholic Fatty liver disease: the bile Acid-activated farnesoid x receptor as an emerging treatment target.
Fuchs M. Fuchs M. J Lipids. 2012;2012:934396. doi: 10.1155/2012/934396. Epub 2011 Dec 7. J Lipids. 2012. PMID: 22187656 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases