title: Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α.
abstract: OBJECTIVE
  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.
authors: Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors: Kai-Ting
authors: KT
authors: Chen
authors: Inserm UMR 991, Université de Rennes 1, Faculté de médecine, F-35043 Rennes cedex, France.
authors: Kelig
authors: K
authors: Pernelle
authors: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors: Yuan-Hau
authors: YH
authors: Tsai
authors: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors: Yu-Hsuan
authors: YH
authors: Wu
authors: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors: Jui-Yu
authors: JY
authors: Hsieh
authors: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors: Ko-Hsun
authors: KH
authors: Liao
authors: Inserm UMR 991, Université de Rennes 1, Faculté de médecine, F-35043 Rennes cedex, France; Biopredic international, Parc d'activité Bretèche batA4, 35760 Saint-Grégoire, France.
authors: Christiane
authors: C
authors: Guguen-Guillouzo
authors: Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; YM-VGH Genome Research Center, National Yang-Ming University, Taipei, Taiwan; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan. Electronic address: hwwang@ym.edu.tw.
authors: Hsei-Wei
authors: HW
authors: Wang
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D017690:Cell Transplantation; D004195:Disease Models, Animal; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D017093:Liver Failure / Q000139:chemically induced / Q000628:therapy; D008115:Liver Regeneration / Q000502:physiology; D000071518:Liver X Receptors; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D002251:Carbon Tetrachloride
keywords: HNF4A; HepaRG progenitor cell; Hepatogenesis; LXRα/NR1H3