NR1H4
MIM.603826 12q
The farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver, intestine, kidney and adipose tissue.
By regulating the expression and function of genes involved in bile acid (BA) synthesis, uptake and excretion, FXR has emerged as a key gene involved in the maintenance of cholesterol and BA homeostasis.
FXR ligands are currently under clinical investigation for the treatment of cholestasis, dyslipidemic disorders and conditions of insulin resistance in type 2 diabetes and non-alcoholic steatohepatitis (NASH).
Because activation of FXR impacts a considerable number of genes, development of FXR modulators that selectively regulate specific pathways will limit potentially undesirable side effects.
Interaction of FXR with other BAs and xenobiotics sensors such as the constitutive androstane receptor and the pregnane X receptor might allow the development of combination therapies for liver and metabolic disorders.
Nuclear hormone receptors
Nuclear hormone receptors play critical roles in many aspects of development and physiology by transducing the effects of hormones into transcriptional responses.
Members of the nuclear receptor family share several structural features, including a central, highly conserved DNA-binding domain (DBD) that targets the receptor to specific DNA sequences, termed hormone response elements (HRE).
The C-terminal portion of the receptor includes the ligand-binding domain (LBD), which interacts directly with the hormone and contains a hormone-dependent transcriptional activation domain.
The LBD serves as a molecular switch that recruits coactivator proteins and activates the transcription of target genes when flipped into the active conformation by hormone binding.
References
Fiorucci S, Rizzo G, Donini A, Distrutti E, Santucci L. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med. 2007 Jul;13(7):298-309. Epub 2007 Jun 27. PMID: 17588816
Alvarez, L.; Jara, P.; Sanchez-Sabate, E.; Hierro, L.; Larrauri, J.; Diaz, M. C.; Camarena, C.; De la Vega, A.; Frauca, E.; Lopez-Callazo, E.; Lapunzina, P. : Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum. Molec. Genet. 13: 2451-2460, 2004. PubMed ID : 15317749