Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia

Benjamin L. Shneider, Victor L. Fox, Kathleen B. Schwarz, Carol L. Watson, Meenakshisundaram Ananthanarayanan, Sundararajah Thevananther, Donna M. Christie, Winita Hardikar, Kenneth D.R. Setchell, Giorgina Mieli-Vergani, Frederick J. Suchy, Alex P. Mowat

Research output: Contribution to journalArticle

Abstract

The recent cloning of a human sodium-dependent bile acid transporter (NTCP) permits analysis of its expression in human liver disease and investigation of potential primary defects in its expression. NTCP from normal human liver (NHL) was first characterized in detail. Northern blotting of RNA from NHL revealed a 1.8-kb NTCP transcript. Western blotting of crude NHL plasma membranes using a carboxyterminal antipeptide antibody showed that NTCP is a 39-kd polypeptide that is N-glycosylated to a final molecular weight of 56 kd. Indirect immunofluorescent analysis of NHL sections indicated that the NTCP protein is expressed on the basolateral surface of hepatocytes. We hypothesized that the clinical phenotype of a defect in NTCP might be hypercholanemia in the relative absence of liver disease. Accordingly, the coding region of the NTCP gene of two children with this phenotype was sequenced after reverse transcription/polymerase chain reaction (RT/PCR) amplification. No primary defects in the deduced NTCP amino acid sequence were found. Despite the extremely high serum bile salt levels (235 and 126 μmol/L) in these two patients, NTCP messenger RNA (mRNA) and protein expression were quantitatively normal, in contrast to the published observations in a rat model of cholestasis secondary to common bile duct ligation. Hepatic steady-state NTCP mRNA levels in a group of 23 pre- and postportoenterostomy biliary atresia patients were inversely related to total bilirubin, indicating that extrahepatic bile duct obstruction leads to down- regulation of NTCP mRNA levels, similar to that observed in rat common bile duct ligation. Therefore the lack of downregulation in the two patients with hypercholanemia indicates that elevated serum bile salts are not sufficient to down-regulate NTCP expression, these two patients have abnormal responses to hypercholanemia, or these two patients have a defect in a gene other than NTCP that influences hepatic clearance of bile salts.

Original languageEnglish (US)
Pages (from-to)1176-1183
Number of pages8
JournalHepatology
Volume25
Issue number5
DOIs
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Hepatology

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    Shneider, B. L., Fox, V. L., Schwarz, K. B., Watson, C. L., Ananthanarayanan, M., Thevananther, S., Christie, D. M., Hardikar, W., Setchell, K. D. R., Mieli-Vergani, G., Suchy, F. J., & Mowat, A. P. (1997). Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia. Hepatology, 25(5), 1176-1183. https://doi.org/10.1002/hep.510250521