Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6ZGS9 (Farnesoid X receptor)
 212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and bile salt export pump (BSEP) disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.
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PMID:Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. 1531 49

Farnesoid X receptor (FXR) is a bile acid-sensing nuclear receptor that controls bile acid homeostasis. It has been suggested that downregulation of FXR contributes to the pathogenesis of an inherited disorder of bile secretion caused by mutations in ATP8B1. We have investigated the relationship between ATP8B1 knockdown and FXR downregulation in the human hepatoblastoma cell line HepG2. Transfection of HepG2 cells with ATP8B1 small interfering RNA (siRNA) duplexes led to a 60% reduction in the endogenous levels of ATP8B1 mRNA and protein and a concomitant decrease in FXR mRNA and protein content, as well as in FXR phosphorylation. This decrease was accompanied by a marked reduction in mRNA levels of a subset of FXR targets, such as bile salt export pump (ABCB11), small heterodimer partner, and uridine 5'-diphosphate-glucuronosyltransferase. ATP8B1 inhibition specifically targeted FXR since mRNA expression of other prominent nuclear receptors, such as pregnane X receptor and constitutive androstane receptor, or liver-enriched transcription factors, such as hepatocyte nuclear factor 1alpha (HNF-1alpha) and HNF-4alpha, was not altered. The expression of other key genes involved in bile acid synthesis, detoxification, and transport also remained unchanged upon ATP8B1 knockdown. Supporting the specificity of the effect, siRNA-mediated silencing of ABCB11, whose defect is associated with another inherited disorder of bile secretion, did not affect FXR expression. Treatment with the synthetic FXR agonist GW4064 was able to partially neutralize ATP8B1 siRNA-mediated FXR downregulation and fully counteract inhibition of FXR target genes. Collectively these findings indicate that ATP8B1 knockdown specifically downregulates FXR, and this action can be circumvented by treatment with FXR agonists.
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PMID:Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064. 1922 86

Alpha-naphthyl isothiocyanate (ANIT) is a hepatotoxicant that produces acute intrahepatic cholestasis in rodents. Farnesoid X receptor (FXR) and pregnane X receptor (PXR) are two major bile acid sensors in liver. The purpose of this study was to characterize the regulation of hepatic transporters by FXR and PXR during ANIT-induced liver injury. Wild-type, FXR-null, and PXR-null mice were administered ANIT (75 mg/kg, po) and evaluated 48 h later for hepatotoxicity and messenger RNA (mRNA) expression of basolateral uptake (sodium taurocholate-cotransporting polypeptide, organic anion transporting polypeptide [Oatp] 1a1, Oatp1a4, Oatp1b2) and efflux transporters (organic solute transporter [Ost] alpha, Ostbeta, multidrug resistance-associated protein [Mrp] 3, Mrp4), as well as canalicular transporters (bile salt export pump [Bsep], Mrp2, multidrug resistance protein 2 [Mdr2], ATPase, class I, type 8B, member 1 [Atp8b1]). Livers from wild-type and PXR-null mice had comparable multifocal necrosis 48 h after ANIT. However, ANIT-treated FXR-null mice have fewer and smaller necrotic foci than wild-type mice but had scattered single-cell hepatocyte necrosis throughout the liver. Serum alanine transaminase, alkaline phosphatase (ALP), and direct bilirubin were increased in all genotypes, with higher ALP levels in FXR-null mice. Serum and liver unconjugated bile acids were higher in ANIT-treated FXR-null mice than the other two genotypes. ANIT induced mRNA expression of Mdr2, Bsep, and Atp8b1 in wild-type and PXR-null mice but failed to upregulate these genes in FXR-null mice. mRNA expression of uptake transporters declined in livers of all genotypes following ANIT treatment. ANIT increased Ostbeta and Mrp3 mRNA in livers of wild-type and PXR-null mice but did not alter Ostbeta mRNA in FXR-null mice. In conclusion, FXR deficiency enhances susceptibility of mice to ANIT-induced liver injury, likely a result of impaired induction of hepatobiliary efflux transporters and subsequent hepatic accumulation of unconjugated bile acids.
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PMID:Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. 1940 37

Farnesoid X receptor (FXR, NR1H4) controls bile acid homeostasis. NR1H4 variants may predispose to intrahepatic cholestasis of pregnancy (ICP). We report on NR1H4 analysis in eight patients with progressive familial intrahepatic cholestasis (PFIC) and in eight women with either ICP and/or drug-induced cholestasis (DIC) in whom no disease causing mutation in ATP8B1, ABCB11 and/or ABCB4 were found. No NR1H4 mutation was found in PFIC patients. In one woman with ICP/DIC, a NR1H4 heterozygous variant (c.-1G>T) was found. This suggests that a NR1H4 mutation is not or rarely involved in hepatocellular cholestasis of unknown cause.
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PMID:NR1H4 analysis in patients with progressive familial intrahepatic cholestasis, drug-induced cholestasis or intrahepatic cholestasis of pregnancy unrelated to ATP8B1, ABCB11 and ABCB4 mutations. 2314 91