Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

JOURNAL OF HEPATOLOGY

卷:61

Article

Chen, Kai-Ting^1,2,3,4  Pernelle, Kelig⁵  Tsai, Yuan-Hau³  Wu, Yu-Hsuan³  Hsieh, Jui-Yu³  Liao, Ko-Hsun³  Guguen-Guillouzo, Christiane^5,6  Wang, Hsei-Wei^1,2,3,7,8 

[1] Natl Yang Ming Univ, Taiwan Int Grad Program Mol Med, Taipei 112, Taiwan

[2] Acad Sinica, Taipei 115, Taiwan

[3] Natl Yang Ming Univ, Inst Microbiol & Immunol, Taipei 112, Taiwan

[4] Natl Yang Ming Univ, Inst Biochem & Mol Biol, Taipei 112, Taiwan

[5] Univ Rennes 1, Inserm, UMR 991, F-35043 Rennes, France

[6] Biopred Int, F-35760 St Gregoire, France

[7] Natl Yang Ming Univ, YM VGH Genome Res Ctr, Taipei 112, Taiwan

[8] Taipei City Hosp, Dept Educ & Res, Taipei, Taiwan

关键词: Hepatogenesis;    LXR alpha/NR1H3;    HNF4A;    HepaRG progenitor cell;   

DOI  :  10.1016/j.jhep.2014.07.025

来源: Elsevier

【 摘 要 】

Background & Aims: Hepatocyte-like cells, differentiated from different stem cell sources, are considered to have a range of possible therapeutic applications, including drug discovery, metabolic disease modelling, and cell transplantation. However, little is known about how stem cells differentiate into mature and functional hepatocytes. Methods: Using transcriptomic screening, a transcription factor, liver X receptor a (NR1H3), was identified as increased during HepaRG cell hepatogenesis; this protein was also upregulated during embryonic stem cell and induced pluripotent stem cell differentiation. Results: Overexpressing NR1H3 in human HepaRG cells promoted hepatic maturation; the hepatocyte-like cells exhibited various functions associated with mature hepatocytes, including cytochrome P450 (CYP) enzyme activity, secretion of urea and albumin, upregulation of hepatic-specific transcripts and an increase in glycogen storage. Importantly, the NR1H3-derived hepatocyte-like cells were able to rescue lethal fulminant hepatic failure using a non-obese diabetic/severe combined immunodeficient mouse model. Conclusions: In this study, we found that NR1H3 accelerates hepatic differentiation through an HNF4 alpha-dependent reciprocal network. This contributes to hepatogenesis and is therapeutically beneficial to liver disease. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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