Disease relevance of Slc10a1

• Expression of Ntcp is reduced in various experimental models of cholestasis associated with increased plasma bile salt concentrations [1].
• The present study further characterizes the expression of multidrug resistance-associated proteins 1-4 (Mrp1-4), breast cancer resistance protein (Bcrp) and sodium-taurocholate co-transporting polypeptide (Ntcp) in mouse liver following administration of the hepatotoxicants acetaminophen (APAP) and carbon tetrachloride (CCl4) [2].

High impact information on Slc10a1

• Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations [3].
• The defects in glycogen storage and serum bile acids coincide with diminished postnatal expression of hepatocyte genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glycogen synthase) and sinusoidal bile acid uptake (Ntcp), respectively [4].
• No changes were seen in the protein mass of BS transporters Ntcp and Bsep [5].
• The ileal apical sodium bile acid cotransporter participates in the enterohepatic circulation of bile acids [6].
• Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice [7].

Biological context of Slc10a1

• The down-regulation of Ntcp1 (Slc10a1) protein expression might protect hepatocytes from high intracellular bile-salt loads [8].
• To isolate the murine Na+/taurocholate cotransporting polypeptide (Ntcp), we screened a mouse liver cDNA library and identified Ntcp1, encoding a 362 amino acid protein and Ntcp2, encoding a 317 amino acid protein which had a shorter C-terminal end [9].

Anatomical context of Slc10a1

• Ntcp protein levels were 4-6-fold reduced in plasma membranes of (-/-) mice relative to sex-matched controls [1].
• A weak cytostatic effect of BANB-1, BANB-2 and BANB-3 was detected even in CHO cells stably transfected with rat bile acid transporters (Ntcp and Oatp1/1a1) [10].
• To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls [11].

Associations of Slc10a1 with chemical compounds

• The bile salt uptake system Na(+)-taurocholate co-transporting polypeptide (Ntcp) and organic anion transporting polypeptide-1 (Oatp1) were down-regulated by taurocholate and not affected by cholestyramine feeding [12].
• Bile acid-induced, farnesoid X receptor (FXR)-mediated induction of the nuclear repressor short heterodimer partner (SHP) has been proposed as a key mechanism reducing Ntcp expression [13].
• All cysteines of mouse ileal and hepatic sodium-dependent bile acid transporters (Isbt and Ntcp, respectively) were individually replaced by alanine [14].
• Ntcp levels were preserved in APAP-exposed livers and reduced to 30-50% of control after CCl4 [2].

Other interactions of Slc10a1

• CONCLUSIONS: Large variations in hepatic bile salt flux have minor effects on expression of murine Ntcp and Bsep in vivo, suggesting that these transporters are abundantly expressed and able to accommodate a wide range of 'physiological' bile salt fluxes [12].
• Cyp7A(-/-) mice did not show altered Ntcp or Oatp1 expression [12].
• However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear [13].
• CONCLUSIONS: Elevated plasma bile salt levels in mdr2 P-glycoprotein-deficient mice in the absence of overt cholestasis are associated with reduced Ntcp expression and transport activity [1].
• Of these, the ileal sodium bile acid transporter (isbt) and the hepatic sodium bile acid cotransporting polypeptide (ntcp) may be most important in determining the efficiency of bile acid recovery within the enterohepatic circulation [15].

Analytical, diagnostic and therapeutic context of Slc10a1

• Northern blot analysis and competitive reverse transcription-polymerase chain reaction were used to determine hepatic Ntcp mRNA levels [1].
• Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR [16].
• Molecular cloning and functional characterization of two alternatively spliced Ntcp isoforms from mouse liver1 [9].
• In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy [11].

References