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

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 differenti...

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Published inJournal of hepatology Vol. 61; no. 6; pp. 1276 - 1286
Main Authors Chen, Kai-Ting, Pernelle, Kelig, Tsai, Yuan-Hau, Wu, Yu-Hsuan, Hsieh, Jui-Yu, Liao, Ko-Hsun, Guguen-Guillouzo, Christiane, Wang, Hsei-Wei
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 01.12.2014
Elsevier
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Summary: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 α (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 HNF4α-dependent reciprocal network. This contributes to hepatogenesis and is therapeutically beneficial to liver disease.
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ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2014.07.025