The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a
nuclear receptor that is encoded by the NR1H4 gene in humans.[5][6]
Function
FXR is expressed at high levels in the liver and intestine.
Chenodeoxycholic acid and other
bile acids are natural
ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the
cell nucleus, forms a
dimer (in this case a heterodimer with
RXR) and binds to
hormone response elements on DNA, which up- or down-regulates the expression of certain
genes.[6]
One of the primary functions of FXR activation is the suppression of
cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from
cholesterol. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of
small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. FXR likewise stimulates the synthesis of
fibroblast growth factor 19, which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase (
CYP8B1) via
fibroblast growth factor receptor 4. In this way, a
negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.[7]
The absence of FXR in an FXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development of
liver tumors.[8] Reducing the pool of bile acids in the FXR-/- mice by feeding the bile acid sequestering resin
cholestyramine reduced the number and size of the malignant lesions.
^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
^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): 605–24.
doi:
10.2174/156802612799436678.
PMID22242859.
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM (May 1999). "Bile acids: natural ligands for an orphan nuclear receptor". Science. 284 (5418): 1365–8.
Bibcode:
1999Sci...284.1365P.
doi:
10.1126/science.284.5418.1365.
PMID10334993.
Bramlett KS, Yao S, Burris TP (Dec 2000). "Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids". Molecular Genetics and Metabolism. 71 (4): 609–15.
doi:
10.1006/mgme.2000.3106.
PMID11136553.
Chamoli, M., Rane, A., Foulger, A. et al. A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan. Nat Aging (2023).
https://doi.org/10.1038/s43587-023-00524-9
The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a
nuclear receptor that is encoded by the NR1H4 gene in humans.[5][6]
Function
FXR is expressed at high levels in the liver and intestine.
Chenodeoxycholic acid and other
bile acids are natural
ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the
cell nucleus, forms a
dimer (in this case a heterodimer with
RXR) and binds to
hormone response elements on DNA, which up- or down-regulates the expression of certain
genes.[6]
One of the primary functions of FXR activation is the suppression of
cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from
cholesterol. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of
small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. FXR likewise stimulates the synthesis of
fibroblast growth factor 19, which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase (
CYP8B1) via
fibroblast growth factor receptor 4. In this way, a
negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.[7]
The absence of FXR in an FXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development of
liver tumors.[8] Reducing the pool of bile acids in the FXR-/- mice by feeding the bile acid sequestering resin
cholestyramine reduced the number and size of the malignant lesions.
^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
^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): 605–24.
doi:
10.2174/156802612799436678.
PMID22242859.
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM (May 1999). "Bile acids: natural ligands for an orphan nuclear receptor". Science. 284 (5418): 1365–8.
Bibcode:
1999Sci...284.1365P.
doi:
10.1126/science.284.5418.1365.
PMID10334993.
Bramlett KS, Yao S, Burris TP (Dec 2000). "Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids". Molecular Genetics and Metabolism. 71 (4): 609–15.
doi:
10.1006/mgme.2000.3106.
PMID11136553.
Chamoli, M., Rane, A., Foulger, A. et al. A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan. Nat Aging (2023).
https://doi.org/10.1038/s43587-023-00524-9