Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
Biochem Pharmacol. 2013 Aug 1;86(3):437-45. doi: 10.1016/j.bcp.2013.05.020. Epub 2013 Jun 6.
Organic anion transporting polypeptides (human: OATPs; rodent: Oatps) were thought to have important functions in bile acid (BA) transport. Oatp1a1, 1a4, and 1b2 are the three major Oatp1 family members in rodent liver. Our previous studies have characterized the BA homeostasis in Oatp1a1-null and Oatp1b2-null mice. The present study investigated the physiological role of Oatp1a4 in BA homeostasis by using Oatp1a4-null mice. Oatp1a4 expression is female-predominant in livers of mice, and thereby it was expected that female Oatp1a4-null mice will have more prominent changes than males. Interestingly, the present study demonstrated that female Oatp1a4-null mice had no significant alterations in BA concentrations in serum or liver, though they had increased mRNA of hepatic BA efflux transporters (Mrp4 and Ostα/β) and ileal BA transporters (Asbt and Ostα/β). In contrast, male Oatp1a4-null mice showed significantly altered BA homeostasis, including increased concentrations of deoxycholic acid (DCA) in serum, liver and intestinal contents. After feeding a DCA-supplemented diet, male but not female Oatp1a4-null mice had higher concentrations of DCA in serum and livers than their WT controls. This suggested that Oatp1a4 is important for intestinal absorption of secondary BAs in male mice. Furthermore, loss of Oatp1a4 function did not decrease BA accumulation in serum or livers of bile-duct-ligated mice, suggesting that Oatp1a4 is not likely a BA uptake transporter. In summary, the present study for the first time demonstrates that Oatp1a4 does not appear to mediate the hepatic uptake of BAs, but plays an important male-predominant role in secondary BA metabolism in mice.
有机阴离子转运多肽（人：OATPs；鼠：Oatps）被认为在胆汁酸（BA）转运中具有重要功能。Oatp1a1、1a4 和 1b2 是鼠肝中 Oatp1 家族的三个主要成员。我们之前的研究已经描述了 Oatp1a1 缺失和 Oatp1b2 缺失小鼠的 BA 动态平衡。本研究通过使用 Oatp1a4 缺失小鼠研究了 Oatp1a4 在 BA 动态平衡中的生理作用。Oatp1a4 在小鼠肝脏中的表达以雌性为主，因此预计雌性 Oatp1a4 缺失小鼠的变化比雄性更为明显。有趣的是，本研究表明，尽管雌性 Oatp1a4 缺失小鼠肝脏中 BA 外排转运蛋白（Mrp4 和 Ostα/β）和回肠 BA 转运蛋白（Asbt 和 Ostα/β）的 mRNA 增加，但血清或肝脏中的 BA 浓度没有明显变化。相比之下，雄性 Oatp1a4 缺失小鼠的 BA 动态平衡发生了显著改变，包括血清、肝脏和肠内容物中脱氧胆酸（DCA）浓度增加。在用 DCA 补充饮食喂养后，雄性而非雌性 Oatp1a4 缺失小鼠的血清和肝脏中 DCA 浓度高于其 WT 对照。这表明 Oatp1a4 对雄性小鼠的次级 BAs 肠吸收很重要。此外，Oatp1a4 功能缺失并未降低胆管结扎小鼠血清或肝脏中 BA 的积累，表明 Oatp1a4 不太可能是 BA 摄取转运体。总之，本研究首次表明，Oatp1a4 似乎不介导 BA 的肝脏摄取，但在小鼠次级 BA 代谢中发挥重要的雄性优势作用。
