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

Abstract：

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.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Chen KT,Pernelle K,Tsai YH,Wu YH,Hsieh JY,Liao KH,Guguen-Guillouzo C,Wang HW

doi

10.1016/j.jhep.2014.07.025

subject

Has Abstract

pub_date

2014-12-01 00:00:00

pages

1276-86

issue

6

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(14)00524-8

journal_volume

61

pub_type

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