Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells.

Autor:	Lyall MJ; University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Cartier J; University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Thomson JP; MRC Human Genetics Unit, IGMM, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK., Cameron K; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Meseguer-Ripolles J; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., O'Duibhir E; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Szkolnicka D; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Villarin BL; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Wang Y; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Blanco GR; Phenome Centre Birmingham, School of Biosciences and Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Dunn WB; Phenome Centre Birmingham, School of Biosciences and Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Meehan RR; MRC Human Genetics Unit, IGMM, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK., Hay DC; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK davehay@talktalk.net., Drake AJ; University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK mandy.drake@ed.ac.uk.
Jazyk:	angličtina
Zdroj:	Philosophical transactions of the Royal Society of London. Series B, Biological sciences [Philos Trans R Soc Lond B Biol Sci] 2018 Jul 05; Vol. 373 (1750).
DOI:	10.1098/rstb.2017.0362
Abstrakt:	Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in developed countries. An in vitro NAFLD model would permit mechanistic studies and enable high-throughput therapeutic screening. While hepatic cancer-derived cell lines are a convenient, renewable resource, their genomic, epigenomic and functional alterations mean their utility in NAFLD modelling is unclear. Additionally, the epigenetic mark 5-hydroxymethylcytosine (5hmC), a cell lineage identifier, is rapidly lost during cell culture, alongside expression of the Ten-eleven-translocation ( TET ) methylcytosine dioxygenase enzymes, restricting meaningful epigenetic analysis. Hepatocyte-like cells (HLCs) derived from human embryonic stem cells can provide a non-neoplastic, renewable model for liver research. Here, we have developed a model of NAFLD using HLCs exposed to lactate, pyruvate and octanoic acid (LPO) that bear all the hallmarks, including 5hmC profiles, of liver functionality. We exposed HLCs to LPO for 48 h to induce lipid accumulation. We characterized the transcriptome using RNA-seq, the metabolome using ultra-performance liquid chromatography-mass spectrometry and the epigenome using 5-hydroxymethylation DNA immunoprecipitation (hmeDIP) sequencing. LPO exposure induced an NAFLD phenotype in HLCs with transcriptional and metabolomic dysregulation consistent with those present in human NAFLD. HLCs maintain expression of the TET enzymes and have a liver-like epigenome. LPO exposure-induced 5hmC enrichment at lipid synthesis and transport genes. HLCs treated with LPO recapitulate the transcriptional and metabolic dysregulation seen in NAFLD and additionally retain TET expression and 5hmC. This in vitro model of NAFLD will be useful for future mechanistic and therapeutic studies.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'. (© 2018 The Authors.)
Databáze:	MEDLINE
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