Universität zu Köln

Rodrigues, Robim M., Branson, Steven, De Boe, Veerle, Sachinidis, Agapios, Rogiers, Vera ORCID: 0000-0003-0635-7740, De Kock, Joery ORCID: 0000-0002-4078-4896 and Vanhaecke, Tamara ORCID: 0000-0002-6685-7299 (2016). In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch. Toxicol., 90 (3). S. 677 - 690. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

Steatosis, also known as fatty liver disease (FLD), is a disorder in which the lipid metabolism of the liver is disturbed, leading to the abnormal retention of lipids in hepatocytes. FLD can be induced by several drugs, and although it is mostly asymptomatic, it can lead to steatohepatitis, which is associated with liver inflammation and damage. Drug-induced liver injury is currently the major cause of postmarketing withdrawal of pharmaceuticals and discontinuation of the development of new chemical entities. Therefore, the potential induction of steatosis must be evaluated during preclinical drug development. However, robust human-relevant in vitro models are lacking. In the present study, we explore the applicability of hepatic cells (hSKP-HPCs) derived from postnatal skin precursors, a stem cell population residing in human dermis, to investigate the steatosis-inducing effects of sodium valproate (Na-VPA). Exposure of hSKP-HPC to sub-cytotoxic concentrations of this reference steatogenic compound showed an increased intracellular accumulation of lipid droplets, and the modulation of key factors involved in lipid metabolism. Using a toxicogenomics approach, we further compared Na-VPA-treated hSKP-HPC and Na-VPA-treated primary human hepatocytes to liver samples from patients suffering from mild and advanced steatosis. Our data show that in hSKP-HPC exposed to Na-VPA and liver samples of patients suffering from mild steatosis, but not in primary human hepatocytes, liver steatosis was efficiently identified as a toxicological response. These findings illustrate the potential of hSKP-HPC as a human-relevant in vitro model to identify hepatosteatotic effects of chemical compounds.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rodrigues, Robim M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Branson, Steven UNSPECIFIED UNSPECIFIED UNSPECIFIED De Boe, Veerle UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Rogiers, Vera UNSPECIFIED orcid.org/0000-0003-0635-7740 UNSPECIFIED De Kock, Joery UNSPECIFIED orcid.org/0000-0002-4078-4896 UNSPECIFIED Vanhaecke, Tamara UNSPECIFIED orcid.org/0000-0002-6685-7299 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-283570
DOI:	10.1007/s00204-015-1483-z
Journal or Publication Title:	Arch. Toxicol.
Volume:	90
Number:	3
Page Range:	S. 677 - 690
Date:	2016
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NONALCOHOLIC STEATOHEPATITIS; DISEASE; HEPATOCYTES; HEPATOTOXICITY; TETRACYCLINE; TOXICOLOGY; INDUCTION; OUTCOMES; INJURY; TOOL Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28357