Regulation of hepatocyte bile salt transporters during hepatic regeneration.

Abstract

Bile formation is an essential liver-specific function, and the hepatic regeneration that occurs in response to hepatocellular injury is often associated with cholestasis. We have employed a partial hepatectomy model to examine the effect of hepatic regeneration on tissue-specific bile salt transporters and on Na(+)-K(+)-adenosinetriphosphatase (ATPase). Liver-specific sodium-dependent taurocholate uptake by basolateral plasma membrane vesicles was undetectable 24 h after hepatectomy. Basolateral membrane protein expression of the sodium-taurocholate cotransporter and gene expression of Ntcp were decreased by > 90% 24 h after partial hepatectomy. In vitro transcription assays demonstrated that Ntcp gene transcription was also markedly reduced. In contrast, hepatic Na(+)-K(+)-ATPase activity, protein expression, and gene expression were unaffected by partial hepatectomy. Similarly, protein and gene expression of the ectoATPase, a putative canalicular bile salt transporter, and canalicular ATP-dependent taurocholate uptake remained unchanged. Partial hepatectomy results in a marked reduction in the gene transcription and expression of the liver-specific Ntcp, as well as a decrease in protein expression and loss of transport activity. These changes provide a potential mechanism for the decrease in hepatocellular bile salt transport that is associated with hepatic regeneration.