Human Bile Salt Export Pump Promoter Is Transactivated by the Farnesoid X Receptor/Bile Acid Receptor

Ananthanarayanan, Meenakshisundaram; Balasubramanian, Niranjan; Makishima, Makoto; Mangelsdorf, David J.; Suchy, Frederick J.

doi:10.1074/jbc.m011610200

Cited by 691 publications

(507 citation statements)

References 42 publications

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“…This transcription factor acts as an intracellular bile salt sensor in hepatocytes and, upon activation by bile salts, binds as a heterodimer with retinoid X receptor (RXR) to the Bsep promoter. This leads to an upregulation of Bsep expression and consequently to increased canalicular bile salt secretion [3,32]. These data are supported by a reduced expression of Bsep in mice lacking the gene for FXR [85].…”

Section: Ontogenesis and Regulationmentioning

confidence: 73%

The bile salt export pump

Stieger

Meier

2006

Pflugers Arch - Eur J Physiol

207

137

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Section: Ontogenesis and Regulationmentioning

confidence: 73%

The bile salt export pump

Stieger

Meier

2006

Pflugers Arch - Eur J Physiol

207

137

View full text Add to dashboard Cite

“…31 However, while CYP7A1 and ASBT were downregulated to a similar extent in all three types of cholestatic diseases, NTCP was downregulated to a lesser extent in PFIC1 than in PFIC2 or biliary atresia. Conversely, the mRNA levels of BSEP, a direct FXR target gene in hepatocytes, 11 were maintained at higher levels in PFIC1 than in the other cholestatic diseases. While we cannot exclude altered transcriptional activity of the FXR/SHP pathway in PFIC1, the circulating bile salt pool composition, which plays a critical role in determining the nuclear activation state of FXR, 32 undergoes changes which may be less dramatic in PFIC1 than in PFIC2 or biliary atresia, and may account for these differences.…”

Section: Discussionmentioning

confidence: 99%

“…12 In response to elevated bile salt levels, FXR is activated, which subsequently stimulates BSEP expression in the liver and represses ASBT expression in the intestine. 11,12 This latter effect is mediated by the small heterodimer partner (SHP), a gene repressor induced by FXR. 12 It has been previously shown that loss of ATP8B1 in the ileum of patients with PFIC1 impaired FXR expression and activation, leading to an overexpression of ASBT, which would presumably cause intestinal bile salt hyperabsorption in these subjects.…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

“…FXR is a nuclear receptor for bile salts and a key transcriptional regulator of genes involved in the synthesis, conjugation and transport of bile salts, in the liver and in the intestine. 10 FXR regulates the expression of BSEP 11 and of the apical sodium-dependent bile salt transporter (ASBT), a protein involved in the intestinal absorption of bile salts. 12 In response to elevated bile salt levels, FXR is activated, which subsequently stimulates BSEP expression in the liver and represses ASBT expression in the intestine.…”

Section: P Rogressive Familial Intrahepatic Cholestasis (Pfic)mentioning

confidence: 99%

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Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

et al. 2006

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Recent reports in patients with PFIC1 have indicated that a gene defect in ATP8B1 could cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. This study aimed to: (1) define ATP8B1 expression in human hepatobiliary cell types, and (2) determine whether ATP8B1 defect affects gene expressions related to bile secretion in these cells. ATP8B1 expression was detected by RT-PCR in hepatocytes and cholangiocytes isolated from normal human liver and gallbladder. ATP8B1 mRNA levels were 20-and 200-fold higher in bile duct and gallbladder epithelial cells, respectively, than in hepatocytes. RT-PCR analyses of the liver from two patients with PFIC1, one with PFIC2, one with biliary atresia, showed that, compared to normal liver, hepatic expressions of FXR, SHP, CYP7A1, ASBT were decreased at least by 90% in all cholestatic disorders. In contrast, NTCP transcripts were less decreased (by <30% vs. 97%) in PFIC1 as compared with other cholestatic disorders, while BSEP transcripts, in agreement with BSEP immunohistochemical signals, were normal or less decreased (by 50% vs. 97%). CFTR hepatic expression was decreased (by 80%), exclusively in PFIC1, while bile duct mass was not reduced, as ascertained by cytokeratin-19 immunolabeling. In Mz-ChA-2 human biliary epithelial cells, a significant decrease in CFTR expression was associated with ATP8B1 invalidation by siRNA. In conclusion, cholangiocytes are a major site of ATP8B1 hepatobiliary expression. A defect of ATP8B1 along with CFTR downregulation can impair the contribution of these cells to bile secretion, and potentially explain the extrahepatic cystic fibrosis-like manifestations that occur in PFIC1. (HEPATOLOGY 2006;43:1125-1134 P rogressive familial intrahepatic cholestasis (PFIC) represents a heterogeneous group of inherited disorders, in which cholestasis starts in infancy and generally leads to liver failure in childhood. Three types of PFIC, caused by mutations in three separate genes, are currently recognized. The first two types, PFIC1 and 2, share common phenotypic features, including normal or nearly normal serum ␥-glutamyl transpeptidase activity and little bile duct proliferation, that are unusual in other types of cholestatic liver diseases. 1 In PFIC2, mutations affect the ABCB11 gene, which encodes a bile salt transporter, the canalicular bile salt export pump (BSEP). 2 Thus, a defect in the extrusion of bile salts across the canalicular membrane of hepatocytes is the primary cause of cholestasis in PFIC2. In PFIC1, mutations affect the ATP8B1 gene, which encodes a protein also called FIC1. 3 ATP8B1 protein belongs to a subfamily of P-type adenosine triphosphatases. Two members of this subfamily including ATP8B1 have been reported to mediate aminophospholipid translocation in plasma membranes. 4,5 The physiological function of ATP8B1 protein and the mechanisms by which ATP8B1 deficiency leads to PFIC1 disease remain poorly understood. It was previously shown that ATP8B1 is expressed in different tissues such as th...

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“…39 Recent investigation indicated that the nuclear farnesoid x receptor and oxysterol x receptor bind bile acids, resulting in a positive/negative regulation in the transcription of several gene products. [40][41][42][43][44] However, there is no binding site for these nuclear receptors in the human PLA 2 IIA gene promoter. 39 In addition, UDCA has been reported to have a limited affinity for these nuclear receptors.…”

Section: Discussionmentioning

confidence: 99%