Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model
文献类型：期刊论文
| 作者 | Ni, Xuan1,2; Gao, Yimeng3; Wu, Zhitao1,2; Ma, Leilei1,2; Chen, Chen1,2; Wang, Le1,2; Lin, Yunfei1,2; Hui, Lijian3; Pan, Guoyu1,2
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| 刊名 | Scientific Reports
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| 出版日期 | 2016-12-09 |
| 卷号 | 6 |
| ISSN号 | 2045-2322 |
| DOI | 10.1038/srep38694 |
| 文献子类 | Article |
| 英文摘要 | Drug-induced cholestasis is a leading cause of drug withdrawal. However, the use of primary human hepatocytes (PHHs), the gold standard for predicting cholestasis in vitro, is limited by their high cost and batch-to-batch variability. Mature hepatocyte characteristics have been observed in human induced hepatocytes (hiHeps) derived from human fibroblast transdifferentiation. Here, we evaluated whether hiHeps could biosynthesize and excrete bile acids (BAs) and their potential as PHH alternatives for cholestasis investigations. Quantitative real-time PCR (qRT-PCR) and western blotting indicated that hiHeps highly expressed BA synthases and functional transporters. Liquid chromatography tandem mass spectrometry (LC-MS/ MS) showed that hiHeps produced normal intercellular unconjugated BAs but fewer conjugated BAs than human hepatocytes. When incubated with representative cholestatic agents, hiHeps exhibited sensitive drug-induced bile salt export pump (BSEP) dysfunction, and their response to cholestatic agent-mediated cytotoxicity correlated well with that of PHHs (r(2) = 0.8032). Deoxycholic acid (DCA)-induced hepatotoxicity in hiHeps was verified by elevated aspartate aminotransferase (AST) and gamma-glutamyl-transferase (gamma-GT) levels. Mitochondrial damage and cell death suggested DCA-induced toxicity in hiHeps, which were attenuated by hepatoprotective drugs, as in PHHs. For the first time, hiHeps were reported to biosynthesize and excrete BAs, which could facilitate predicting cholestatic hepatotoxicity and screening potential therapeutic drugs against cholestasis. |
| WOS关键词 | INDUCED LIVER-INJURY ; CULTURED RAT HEPATOCYTES ; DRUG-INDUCED CHOLESTASIS ; PREGNANE-X-RECEPTOR ; HEPARG CELLS ; HEPATOBILIARY TRANSPORTERS ; BILIARY OBSTRUCTION ; DAMAGE ; TOXICITY ; CHOLESTEROL |
| 资助项目 | National Science Foundation of China[81302836] ; National Science Foundation of China[81573499] ; National High Technology Research and Development Program of China[2013AA032202] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000389542300001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275766]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Hui, Lijian; Pan, Guoyu |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Medica, Shanghai 201203, Peoples R China; 3.Shanghai Inst Biol Sci, Chinese Acad Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ni, Xuan,Gao, Yimeng,Wu, Zhitao,et al. Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model[J]. Scientific Reports,2016,6. |
| APA | Ni, Xuan.,Gao, Yimeng.,Wu, Zhitao.,Ma, Leilei.,Chen, Chen.,...&Pan, Guoyu.(2016).Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model.Scientific Reports,6. |
| MLA | Ni, Xuan,et al."Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model".Scientific Reports 6(2016). |
入库方式： OAI收割
来源：上海药物研究所
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