title: In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells.
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.
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium. rmarceli@vub.ac.be.
authors.forename: Robim M
authors.initials: RM
authors.lastname: Rodrigues
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Branson
authors.affiliation: Department of Urology, UZ Brussel, Brussels, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: De Boe
authors.affiliation: Institute of Neurophysiology, Center of Physiology, University of Cologne, Cologne, Germany.
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joery
authors.initials: J
authors.lastname: De Kock
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Tamara
authors.initials: T
authors.lastname: Vanhaecke
mesh_terms: D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced*; D012867:Skin / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D014635:Valproic Acid
keywords: In vitro toxicology; Postnatal stem cells; Steatosis; hSKP