Reactome | NR1H4 binds DCA, CDCA, LCHA

NR1H4 binds DCA, CDCA, LCHA

Stable Identifier

R-HSA-5340195

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

Synonyms

FXR binds bile acids

ReviewStatus

5/5

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The nuclear orphan protein bile acid receptor aka farnesoid X-activated receptor (NR1H4 aka FXR) can be activated by bile acids and their salts, its physiological ligands. Mouse Nrih4 is highly expressed in the liver, intestine, kidney and adrenal gland, and to a lesser extent in white adipose tissue and heart (Zhang et al. 2003). Bile acids tested to activate NR1H4 are chenodeoxycholic acid (CDCA), lithocholic acid (LCHA) and deoxycholic acid (DCA) (Parks et al. 1999, Makishima et al. 1999).

Once bound to its ligand, activated NR1H4 binds to retinoic acid receptor RXR-alpha (RXRA) and either nuclear receptor coactivator 1 or 2 (NCOA1 or 2) to function as a ligand-activated transcription factor. This complex repressed transcription of the CYP7A1 gene (encoding cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in bile acid synthesis) (Holt et al. 2003) and activated the SLC10A2 and 6 genes (encoding Ileal sodium/bile acid cotransporters, both bile acid transporters) (Plass et al. 2002, Ananthanarayanan et al. 2001). Thus, NR1H4 is one of the most important regulators of bile acid metabolism, regulating bile acid synthesis, conjugation, secretion and uptake (Lee et al. 2006, Houten et al. 2006).

Literature References

PubMed ID	Title	Journal	Year
10334992	Identification of a nuclear receptor for bile acids Hull, MV, Lustig, KD, Learned, RM, Okamoto, AY, Makishima, M, Repa, JJ, Mangelsdorf, DJ, Luk, A, Shan, B, Tu, H	Science	1999
11387316	Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor Suchy, FJ, Balasubramanian, N, Mangelsdorf, DJ, Makishima, M, Ananthanarayanan, M	J. Biol. Chem.	2001
16541101	Endocrine functions of bile acids Watanabe, M, Houten, SM, Auwerx, J	EMBO J.	2006
12815072	Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis Goodwin, B, Bisi, J, Holt, JA, Jones, SA, Kliewer, SA, Wang, DY, Luo, G, McNeill, YY, Kozarsky, KF, Billin, AN, Mansfield, TA, Donahee, M	Genes Dev.	2003
10334993	Bile acids: natural ligands for an orphan nuclear receptor Chandra, G, Willson, TM, Bledsoe, RK, Moore, DD, Kliewer, SA, Consler, TG, Lehmann, JM, Blanchard, SG, Zavacki, AM, Parks, DJ, Stimmel, JB	Science	1999
16908160	FXR, a multipurpose nuclear receptor Zhang, Y, Hubbert, ML, Lee, H, Edwards, PA, Lee, FY	Trends Biochem. Sci.	2006
11870371	Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump Mol, O, Plass, JR, Jansen, PL, Faber, KN, Geuken, M, Müller, M, Heegsma, J	Hepatology	2002
12393883	Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation Zhang, Y, Edwards, PA, Kast-Woelbern, HR	J. Biol. Chem.	2003