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在具有患者特异性突变的干细胞衍生的肝细胞中建模人胆汁酸转运和合成。

Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation.

机构信息

Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

出版信息

Stem Cell Reports. 2021 Feb 9;16(2):309-323. doi: 10.1016/j.stemcr.2020.12.008. Epub 2021 Jan 14.

DOI:10.1016/j.stemcr.2020.12.008
PMID:33450190
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7878720/
Abstract

The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.

摘要

胆汁盐输出泵（BSEP）负责将胆汁酸从肝细胞中排出。BSEP 基因突变导致肝细胞内胆汁酸的跨细胞转运受损，引起胆汁淤积。BSEP 缺陷的人肝细胞中调节细胞内胆汁酸浓度的代偿机制尚不清楚。为了明确防止胆汁酸在肝细胞中蓄积产生细胞毒性的途径，我们在 Transwell 培养系统中建立了基于人诱导多能干细胞的同基因 BSEP 缺陷型肝细胞模型。诱导的肝细胞（i-Heps）在胆汁酸的顶侧分泌中存在缺陷，但通过诱导基底外侧分泌，维持了较低的细胞内胆汁酸浓度。通过模拟胆汁酸对肝细胞的自动调节，我们发现 BSEP 缺陷型 i-Heps 通过基底外侧摄取和分泌而不是顶侧分泌，利用 FXR 通路抑制从头合成胆汁酸。这些观察结果为开发治疗靶点提供了信息，以减少 BSEP 缺陷患者的总体胆汁酸池。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/65eff78596dc/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/bfb9bbe3007c/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/0b871a055d58/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/e8762e6f8a39/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/c86e8579ea20/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/8507ba566088/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/613f68fa17fb/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/65eff78596dc/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/bfb9bbe3007c/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/0b871a055d58/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/e8762e6f8a39/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/c86e8579ea20/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/8507ba566088/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/613f68fa17fb/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/538a/7878720/65eff78596dc/gr6.jpg

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