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首页> 外文期刊>Journal of cellular biochemistry. >Functional expression of organic anion transporters in hepatic organoids reconstructed by rat small hepatocytes.
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Functional expression of organic anion transporters in hepatic organoids reconstructed by rat small hepatocytes.

机译：在大鼠小肝细胞重建的肝类器官中有机阴离子转运蛋白的功能性表达。

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Small hepatocytes (SHs) are hepatic progenitor cells with hepatic characteristics. They can proliferate to form colonies in culture and change their morphology from flat to rising/piled-up with bile canaliculi (BC), which results in maturation. In this study, we examined whether SHs could express hepatic transporters with polarity, whether the transporters could transport organic anion substrates into BC, and whether the secreted substances could be recovered from BC. Immunocytochemistry and RT-PCR were carried out. [(3)H]-labeled estrogen derivatives were used to measure the functions of the transporters in SHs isolated from normal and multidrug resistance-associated protein (Mrp) 2-deficient rats. The results showed that organic anion-transporting proteins (Oatps) 1 and 2, Na(+)-dependent taurocholate co-transporting polypeptide (Ntcp), Mrp2, and bile-salt export pump (Bsep) were well expressed in rising/piled-up cells and that their expression was correlated to that of hepatocyte nuclear factor 4alpha. Although small SHs expressed not Oatps and Mrp2 but Mrp3, rising/piled-up SHs expressed Oatp1 and 2 and Mrp2 proteins in the sinusoidal and BC membranes, respectively. On the other hand, breast cancer resistant protein (Bcrp) and Mrp3 expression decreased as SHs matured. The substrate transported via Oatps and Mrp2 was secreted into BC and it accumulated in both BC and cyst-like structures. The secreted substrate could be efficiently recovered from BC reconstructed by SHs derived from a normal rat, but not from an Mrp2-deficient rat. In conclusion, SHs can reconstitute hepatic organoids expressing functional organic anion transporters in culture. This culture system may be useful to analyze the metabolism and excretion mechanisms of drugs.
机译：小肝细胞（SHs）是具有肝特征的肝祖细胞。它们可以在培养物中增殖形成菌落，并通过胆小管（BC）使其形态从扁平状变为上升/堆积状，从而导致成熟。在这项研究中，我们检查了SHs是否可以表达具有极性的肝转运蛋白，这些转运蛋白是否可以将有机阴离子底物转运到BC中，以及分泌的物质是否可以从BC中回收。进行了免疫细胞化学和RT-PCR。 [（3）H]标记的雌激素衍生物用于测量从正常和多药耐药相关蛋白（Mrp）2缺陷大鼠分离的SH中转运蛋白的功能。结果显示，有机阴离子转运蛋白（Oatps）1和2，依赖Na（+）的牛磺胆酸盐共转运多肽（Ntcp），Mrp2和胆盐输出泵（Bsep）在上升/堆积-细胞，并且它们的表达与肝细胞核因子4α的表达相关。虽然小的SH并不表达Oatps和Mrp2，而是表达Mrp3，但上升/堆积的SH分别在正弦和BC膜中表达Oatp1、2和Mrp2蛋白。另一方面，随着SHs的成熟，乳腺癌抗性蛋白（Bcrp）和Mrp3表达下降。通过Oatps和Mrp2转运的底物被分泌到BC中，并且在BC和囊样结构中均积累。分泌的底物可以从正常大鼠（而不是Mrp2缺陷大鼠）的SH重建的BC中有效回收。总之，SHs可以在培养物中重构表达功能性有机阴离子转运蛋白的肝类器官。该培养系统可能有助于分析药物的代谢和排泄机制。

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