The NA/+bile acid cotransporter plays a key role in the active transport of bile acid into liver. The gene encoding the liver Na+/taurocholate cotransporting polypeptide (Ntcp) appears to be specifically expressed in the liver and subject to a number of transcriptional controls. The overall objective of the studies proposed in this application will be to characterize the regulatory mechanisms controlling the tissue-specific expression of the Na+/taurocholate cotransporter, as well as its regulation by specific hormones. The first specific aim proposed is to identify major control regions within the Ntcp promoter region, and to determine which trans-acting factors act as regulators. Experimental procedures will include the use of reporter gene constructs containing putative regulatory regions. Additionally, nucleosome positioning studies will de utilized to identify control regions.
The second aim focuses on characterizing the regulation of Ntcp gene expression by hormonal regulatory controls. We present preliminary evidence indicating that the Na+/taurocholate cotransporter is upregulated by insulin, suggesting implications of bile acid uptake in the relationship between diabetes mellitus and liver disease. Additionally, we suggest that hormones, in particular, growth hormone, estrogen and prolactin regulate Ntcp gene expression. It is the aim of this research to characterized the mechanisms regulating the hormonal control of the Ntcp gene. Thus, the research proposed in this application will lead to a greater understanding of the overall function of the liver and enterohepatic circulation.
