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

Abstract

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 α-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.

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

“…5-fold changes between KO and WT control mice (Supplementary Figures 1B, C and 2). Sexual dimorphism in HFD-induced obesity and metabolic alterations, and hepatic transport of taurocholate have been reported in mice and rats (Simon et al 1999, Nishikawa et al 2007, Hwang et al 2010, Grove et al 2010. In humans, key characteristics of obesity such as pattern of fat accumulation, energy homeostasis, and sensitivity of the brain to adiposity hormones, insulin and leptin, have been shown to be influenced by gender (Woods et al 2003, Regitz-Zagrosek et al 2007.…”

Sex-Dependent Expression and Activity of the ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (BCRP/ABCG2) in Liver

“…The mammalian liver is one example. Sexual differences have been described for hepatic transport as well as for enzymatic activities, drug detoxification, and lipid metabolism (Simon et al, 1999). Many enzymes belonging to the cytochrome P450 superfamily are expressed in the liver in unique, sex-dependent Fig.…”

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).…”

“…There is higher mRNA expression of uptake transport- Li et al, 2002;Cheng et al, 2005a Oatp1a4 F Guo et al, 2002b;Li et al, 2002;Cheng et al, 2005a Oatp1a6 F Ͼ M N.D. Li et al, 2002;Cheng et al, 2005a Oatp2b1 F Simon et al, 1999;Cheng et al, 2007 Abca1 M Ͼ F N.D. Cheng and Klaassen, 2009 Maher et al, 2005b;Rost et al, 2005 Mrp4 F Merino et al, 2005c;Tanaka et al, 2005 Mate1 F Cheng and Klaassen, 2009 Oatp2b1 (jej) M Ͼ F N.D. Cheng et al, 2005a Cnt3 (jej) M Ͼ F N.D. Lu et al, 2004 Ost␣ (jej) M Ͼ F N.D. C. Klaassen et al, unpublished Ost␤ (jej) M Ͼ F N.D. C. Klaassen et al, unpublished Asbt (il) F Ͼ M N.D. Cheng and Klaassen, 2009 Mate2 (LI) M Ͼ F N.D. Lickteig et al, 2008 Abcg5 (jej) M Dieter et al, 2004 M, male; F, female; duo, duodenum; jej, jejunum; il, ileum; LI, large intestine; N.D., not determined.…”

“…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.…”