Thebile acid receptor (BAR), also known asfarnesoid X receptor (FXR) orNR1H4 (nuclear receptor subfamily 1, group H, member 4), is anuclear receptor that is encoded by theNR1H4 gene in humans.[5][6]
FXR is expressed at high levels in the liver and intestine.Chenodeoxycholic acid and otherbile acids are naturalligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to thecell nucleus, forms adimer (in this case a heterodimer withRXR) and binds tohormone response elements on DNA, which up- or down-regulates the expression of certaingenes.[6]
One of the primary functions of FXR activation is the suppression ofcholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis fromcholesterol. FXR does not directly bind to theCYP7A1 promoter. Rather, FXR induces expression ofsmall heterodimer partner (SHP), which then functions to inhibit transcription of theCYP7A1 gene. FXR likewise stimulates the synthesis offibroblast growth factor 19, which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase (CYP8B1) viafibroblast growth factor receptor 4. In this way, anegative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.[7]
The absence of FXR in anFXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development ofliver tumors.[8] Reducing the pool of bile acids in theFXR-/- mice by feeding the bile acid sequestering resincholestyramine reduced the number and size of the malignant lesions.[citation needed]
FXR is an important modulator ofbile acid homeostasis.[11] Loss of FXR or bile-acid dependent inhibition of FXR in progenitor cells at the gastroesophageal junction drives gastroesophagealadenocarcinomacarcinogenesis.[11]
^Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007 Feb 1;67(3):863-7. doi: 10.1158/0008-5472.CAN-06-1078. PMID 17283114
^abBaumeister T, Proaño-Vasco A, Metwaly A, Kleigrewe K, Kuznetsov A, Schömig L, Borgmann M, Khiat M, Anand A, Strangmann J, Böttcher K, Haller D, Dunkel A, Somoza V, Reiter S, Meng C, Thimme R, Schmid RM, Patil DT, Burgermeister E, Huang Y, Sun Y, Wang HH, Wang TC, Abrams JA, Quante M. Loss of FXR or Bile Acid-dependent Inhibition accelerate carcinogenesis of Gastroesophageal Adenocarcinoma. Cell Mol Gastroenterol Hepatol. 2025 Mar 24:101505. doi: 10.1016/j.jcmgh.2025.101505. Epub ahead of print. PMID: 40139565.
^Fiorucci S, Zampella A, Distrutti E (2012). "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders".Current Topics in Medicinal Chemistry.12 (6):605–624.doi:10.2174/156802612799436678.PMID22242859.
^Fiorucci S, Mencarelli A, Distrutti E, Zampella A (May 2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications".Future Medicinal Chemistry.4 (7):877–891.doi:10.4155/fmc.12.41.PMID22571613.
Bramlett KS, Yao S, Burris TP (December 2000). "Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids".Molecular Genetics and Metabolism.71 (4):609–615.doi:10.1006/mgme.2000.3106.PMID11136553.
Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, et al. (May 2002). "Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters".Gene.290 (1–2):35–43.doi:10.1016/S0378-1119(02)00557-7.PMID12062799.
Barbier O, Torra IP, Sirvent A, Claudel T, Blanquart C, Duran-Sandoval D, et al. (June 2003). "FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity".Gastroenterology.124 (7):1926–1940.doi:10.1016/S0016-5085(03)00388-3.PMID12806625.
