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)

Recent studies have elucidated the mechanism and regulation of hepatic transport of bile acids and organic anions. Bile acids are taken up into hepatocytes by basolateral transporters, Na+-dependently by Na+/taurocholate cotransporting polypeptide (NTCP) and Na+-independently by organic anion transporting polypeptide (OATP) families. Organic anions are taken up into hepatocytes by OATP families. These compounds are then transported in hepatocytes bound to cytosolic binders, and subjected to transport by ATP binding cassette (ABC) transporters at the canalicular membrane. Amidated bile acids are excreted into bile by bile salt export pump (BSEP), and organic anions and bile acid sulfates and glucuronides are excreted by multidrug resistance protein 2 (MRP2). Hepatic transporters are downregulated under cholestasis in rats and humans, except for MRP3, a basolateral ABC transporter, which is upregulated and may have a role in removing bile acids and organic anions from hepatocytes to the blood under cholestatic conditions. Nuclear receptors, which bind bile acids, have been shown to regulate the expression of hepatic transporters. Farnesoid X receptor (FXR), which downregulates CYP7A1, the rate-limiting enzyme of bile acid biosynthesis, upregulates BSEP and downregulates NTCP. MRP2 is upregulated by both FXR and pregnane X receptor (PXR), which upregulates CYP3A.
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PMID:Hepatobiliary transport of bile acids and organic anions. 1248 66

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

To characterize the mechanisms of action of taurocholic acid(TCA) and farnesoid X receptor(FXR) on organic anion transporting polypeptide 1A2(OATP1A2) expression in placental Bewo cell line. Quantitative real-time PCR and Western blots were used to detect OATP1A2 in Bewo cells cultured with TCA and pcDNA3.1(+)-hFXR transfected Bewo cells after incubation with 2 mM TCA for 48 hours. TCA(0.02 mM) induced the mRNA and protein expression of OATP1A2 by 3 and 1.6 fold (p<0.05), respectively, while 0.2 and 2 mM TCA induced mRNA and protein expression by 1.5 and 1.3 fold, respectively. The concentration of TCA was negatively correlated with OATP1A2 gene expression (P<0.05). In pcDNA3.1(+)-hFXR transfected Bewo cells with 2 mM TCA demonstrated a 2-3 fold increase in OATP1A2 over controls (P<0.05). TCA is one of the regulation factors for OATP1A2 in the Bewo cell line. A low dose of TCA can induce fetal membrane expression of OATP1A2. This may present a physiological or compensatory mechanism of the placenta, while the high dose of TCA may produce a pathological or pathogenic mechanism. Farnesoid X receptor may act in synergy with TCA to increase the expression of OATP1A2. This may be a treatment strategy for fetal cholestasis.
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PMID:Molecular regulation of organic anion transporting polypeptide 1A2 (OATP1A2)by taurocholic acid in Bewo Cells. 2497 Jan 18