Characterization of the mechanisms involved in the gender differences in hepatic taurocholate uptake
Simon, F.R.; Fortune, J.; Iwahashi, M.; Bowman, S.; Wolkoff, A.; Sutherland, E.
American Journal of Physiology 276(2): G556-G565
1999
ISSN/ISBN: 0002-9513 PMID: 9950831 Document Number: 504356
Gender differences in the hepatic transport of organic anions is well established. Although uptake of many organic anions is greater in females, sodium-dependent taurocholate uptake is greater in hepatocytes from male rats. We examined the hypothesis that endogenous estrogens alter the number of sinusoidal bile acid transporters and/or decrease membrane lipid fluidity. The initial sodium-dependent uptake of taurocholate was 75% greater in hepatocytes from males than from either intact or oophorectomized females rats. Taurocholate maximal uptake was increased twofold (P < 0.03) without a significant change in the Michaelis-Menten constant. Sinusoidal membrane fractions were isolated from male and female rat livers with equal specific activities and enrichments of Na+-K+-ATPase. Males had a significant (P < 0.05) increase in cholesterol esters and phosphatidylethanolamine-to-phosphatidylcholine ratio. Fluorescence polarization indicated decreased lipid fluidity 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 (Oatp) and Na+-K+-ATPase a-subunit were not significantly different. Nuclear run-on analysis indicated a 47% (P < 0.05) decrease in Ntcp transcription, without a significant change in Oatp. In conclusion, these studies demonstrated that decreased sodium-dependent bile salt uptake in female hepatocytes was due to decreased membrane lipid fluidity and a selective decrease in Ntcp. Reprinted by permission of the publisher.