Novel liver‐specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate
Novel liver‐specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate
复制标题
DOI：
10.1002/hep.21596
复制
发表时间：
2007-04
期刊：
影响因子：
13.5
通讯作者：
H. Shin;N. Anzai;A. Enomoto;Xin He;Do Kyung Kim;H. Endou;Y. Kanai
中科院分区：
文献类型：
--
作者：
H. Shin;N. Anzai;A. Enomoto;Xin He;Do Kyung Kim;H. Endou;Y. Kanai
肝脏在消除体内内源性和外源性亲脂性有机化合物方面发挥着重要作用，这一过程是由各种底物特异性和动力学性质不同的载体蛋白介导的。在这里，我们已经鉴定了从人肝脏分离的有机阴离子转运蛋白家族（SLC22）的新成员。有机阴离子转运蛋白7 （OAT7/ SLC22A9）与SLC22家族其他有机阴离子转运蛋白的同源性为35% ~ 46%。当在爪蟾卵母细胞中表达时，OAT7介导了不依赖Na+的硫酸盐结合类固醇、硫酸雌酮（ES, Km = 8.7 μM）和硫酸脱氢表雄酮（Km = 2.2 μM）的高亲和力转运。此外，OAT7还能与带负电荷的磺胺溴眼蛋白、吲哚菁绿和几种硫酸盐偶联的异种生物相互作用。相比之下，葡萄糖醛酸和谷胱甘肽偶联物对OAT7介导的[3H]ES转运没有抑制作用。三碳到五碳（C3到C5）短链脂肪酸可以反式刺激OAT7介导的[3H]ES转运。细胞外ES显著刺激了[14C]丁酸盐（C4）通过OAT7的外排。此外，在非洲爪蟾卵母细胞和稳定表达OAT7的细胞中，OAT7介导了[14C]丁酸盐摄取和[3H]ES外排，以交换细胞外丁酸盐。免疫组化分析表明，OAT7蛋白定位于肝细胞窦膜。结论：OAT7是SLC22家族有机阴离子转运蛋白中首个肝脏特异性转运蛋白。我们的发现为有机阴离子转运体提供了一类新的底物，并为阴离子物质（如硫酸盐偶联物）在肝细胞中转运以换取丁酸盐提供了证据。(肝脏病学45:1046 2007;1055)。
The liver plays an important role in the elimination of endogenous and exogenous lipophilic organic compounds from the body, which is mediated by various carrier proteins that differ in substrate specificity and kinetic properties. Here, we have characterized a novel member of the organic anion transporter family (SLC22) isolated from human liver. The transporter named organic anion transporter 7 (OAT7/ SLC22A9) showed 35% to 46% identities to those of other organic anion transporters of SLC22 family. When expressed in Xenopus oocytes, OAT7 mediated Na+‐independent, high‐affinity transport of sulfate‐conjugated steroids, estrone sulfate (ES; Km = 8.7 μM), and dehydroepiandrosterone sulfate (Km = 2.2 μM). In addition, OAT7 interacted with negatively charged sulfobromophthalein, indocyanine green, and several sulfate‐conjugated xenobiotics. In contrast, glucuronide and glutathione conjugates exhibited no inhibitory effects on OAT7‐mediated [3H]ES transport. OAT7‐mediated [3H]ES transport was trans‐stimulated by three‐carbon to five‐carbon (C3 to C5) short‐chain fatty acids. The efflux of [14C]butyrate (C4) via OAT7 was significantly trans‐stimulated by extracellular ES. Furthermore, OAT7 mediated [14C]butyrate uptake and [3H]ES efflux in exchange for extracellular butyrate both in Xenopus oocytes and OAT7‐stably expressing cells. OAT7 protein was localized in the sinusoidal membrane of hepatocytes by immunohistochemical analysis. Conclusion: OAT7 is the first liver‐specific transporter among members of the organic anion transporters of SLC22 family. Our findings suggest a new class of substrates for organic anion transporters and provide evidence for the transport of anionic substances such as sulfate‐conjugates in exchange for butyrate in hepatocytes. (HEPATOLOGY 2007;45:1046–1055.)