Characterization of the mechanisms involved in the gender differences in hepatic taurocholate uptake

Gender differences in the hepatic transport of organic anions is well estab lished. Although uptake of many organic anions is greater in females, sodiu m-dependent taurocholate uptake is greater in hepatocytes from male rats. W e examined the hypothesis that endogenous estrogens alter the number of sin usoidal bile acid transporters and/or decrease membrane lipid fluidity. The initial sodium-dependent uptake of [H-3]taurocholate was 75% greater in he patocytes from males than from either intact or oophorectomized females rat s. Taurocholate maximal uptake was increased twofold (P < 0.03) without a s ignificant change in the Michaelis-Menten constant. Sinusoidal membrane fra ctions were isolated from male and female rat livers with equal specific ac tivities and enrichments of Na+-K+-ATPase. Males had a significant (P < 0.0 5) increase in cholesterol esters and phosphatidylethanolamine-to-phosphati dylcholine ratio. Fluorescence polarization indicated decreased lipid fluid ity in females. In females, expression of the sodium-dependent taurocholate peptide (Ntcp) and mRNA were selectively decreased to 46 +/- 9 and 54 +/- 4% (P < 0.01), respectively, and the organic anion transporter peptide (Oat p) and Na+-K+-ATPase alpha-subunit were not significantly different. Nuclea r run-on analysis indicated a 47% (P < 0.05) decrease in Ntcp transcription , without a significant change in Oatp. In conclusion, these studies demons trated that decreased sodium-dependent bile salt uptake in female hepatocyt es was due to decreased membrane lipid fluidity and a selective decrease in Ntcp.