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1 Department of Medicine and Denver Veterans Affairs Medical Center, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 2 Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461
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
[3H]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
-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.
lipid composition; lipid fluidity; sodium-dependent taurocholate transporter; organic anion transport peptide; transcription
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