Regulation of hepatic bile acid transporters Ntcp and Bsep expression

Abstract

Sodium-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) are two key transporters for hepatic bile acid uptake and excretion. Alterations in Ntcp and Bsep expression have been reported in pathophysiological conditions. In the present study, the effects of age, gender, and various chemicals on the regulation of these two transporters were characterized in mice. Ntcp and Bsep mRNA levels in mouse liver were low in the fetus, but increased to its highest expression at parturition. After birth, mouse Ntcp and Bsep mRNA decreased by more than 50%, and then gradually increased to adult levels by day 30. Expression of mouse Ntcp mRNA and protein exhibit higher levels in female than male livers, which is consistent with the trend of human NTCP mRNA expression between men and women. No gender difference exists in BSEP/Bsep expression in human and mouse livers. Hormone replacements conducted in gonadectomized, hypophysectomized, and lit/lit mice indicate that female-predominant Ntcp expression in mouse liver is due to the inhibitory effect of male-pattern GH secretion, but not sex hormones. Ntcp and Bsep expression are in general resistant to induction by a large battery of microsomal enzyme inducers. Administration of cholestyramine increased Ntcp, whereas chenodeoxycholic acid increased Bsep mRNA expression. In silico analysis indicates that female-predominant mouse and human Ntcp/NTCP expression may be due to GH. In conclusion, mouse Ntcp and Bsep are regulated by age, gender, cholestyramine, and bile acid, but resistant to induction by most microsomal enzyme inducers.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Male-predominant expression of Oatp1a1, Oat1, and Oct2 is similarly observed in the kidneys of mice and rats (Urakami et al, 1999;Buist et al, 2002;Slitt et al, 2002;Buist and Klaassen, 2004;Alnouti et al, 2006;Groves et al, 2006). In contrast, hepatic Ntcp demonstrates female-predominant mRNA expression in mice and male-predominant expression in rats (Simon et al, 1999;Cheng et al, 2007). There is more NTCP mRNA in female human livers, although it is not statistically significant because of large interindividual variation (Cheng et al, 2007).…”

“…Male (() mRNA is shown on the left, whereas female (Ǩ) mRNA is shown on the right side of each box. References for mouse mRNA expression are included (Dieter et al, 2004;Cheng et al, 2007). Bottom, relative mRNA levels of transporters in human liver, kidneys, lung, heart, brain, testes, ovaries, placenta, and uterus are shown.…”

“…The net effect of these expression patterns favors lower intracellular accumulation of substrates in the renal tubule cells of female mice and could influence rates of chemical secretion and reabsorption. A number of liver transporters demonstrate femalepredominant (Oatp1a4, -1a6, -2b1, Ntcp, Mrp4, Mate1) or male-predominant (Oatp1a1, Bcrp, Abca1) mRNA expression patterns in mice (Simon et al, 1999;Guo et al, 2002a;Li et al, 2002;Cheng et al, 2005aCheng et al, , 2007Maher et al, 2005b;Tanaka et al, 2005;Lickteig et al, 2008). There are relatively fewer sex differences in other mouse tissues.…”

Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression

“…Relative expression of bile saltexport pump (Abcb11, Bsep) and Na + -taurocholate cotransporting polypeptide (Slc10a1, Ntcp) mRNA was quantified using bDNA assay and previously described probe sets (Cheng et al, 2007). All reagents for analysis, including lysis buffer, amplifier/label probe diluent, and substrate solution, were supplied in the QuantiGene 1.0 assay kit (Panomics/Affymetrix eBioscience).…”

“…With regard to transporters, hepatic Abcc2-4 induction by microsomal enzyme inducers is observed to be Nrf2-dependent . Prototypical Pxr activators upregulate hepatic Abcc2, Abcc3, Na + -taurocholate cotransporting polypeptide (Ntcp), and solute-carrier organic anion transporter (Slco)1a4 expression (Cheng et al, , 2007Maher et al, 2005), whereas Car activators upregulate Abcc2-6 mRNA expression in liver Maher et al, 2005). An increase in mRNA expression of these transcription factors was observed in livers of 9-week-old ob/ob mice compared with WT mice (Xu et al, 2012), implicating coordinate regulation of drug-transporter and transcription-factor expression in steatosis.…”