Human skin stem cell-derived hepatic cells as in vitro drug discovery model for insulin-driven de novo lipogenesis.

Autor: Buyl K; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium. Electronic address: Karolien.Buyl@vub.be., Vrints M; Galapagos NV, Industriepark Mechelen Noord, Generaal De Wittelaan L11 A3, B-2880, Mechelen, Belgium., Fernando R; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium., Desmae T; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium., Van Eeckhoutte T; Galapagos NV, Industriepark Mechelen Noord, Generaal De Wittelaan L11 A3, B-2880, Mechelen, Belgium., Jans M; Galapagos NV, Industriepark Mechelen Noord, Generaal De Wittelaan L11 A3, B-2880, Mechelen, Belgium., Van Der Schueren J; Galapagos NV, Industriepark Mechelen Noord, Generaal De Wittelaan L11 A3, B-2880, Mechelen, Belgium., Boeckmans J; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium., Rodrigues RM; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium., De Boe V; Department of Urology, Universitair Ziekenhuis Brussel (UZ-Brussel), Laarbeeklaan 101, B-1090, Brussels, Belgium., Rogiers V; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium., De Kock J; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium., Beirinckx F; Galapagos NV, Industriepark Mechelen Noord, Generaal De Wittelaan L11 A3, B-2880, Mechelen, Belgium., Vanhaecke T; Department of in Vitro Toxicology and Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2023 Oct 15; Vol. 957, pp. 175989. Date of Electronic Publication: 2023 Aug 11.
DOI: 10.1016/j.ejphar.2023.175989
Abstrakt: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by intrahepatic triglyceride accumulation and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Hepatic de novo lipogenesis (DNL), activated by glucose and insulin, is a central pathway contributing to early-stage development of MASLD. The emerging global prevalence of MASLD highlights the urgent need for pharmaceutical intervention to combat this health threat. However, the identification of novel drugs that could inhibit hepatic DNL is hampered by a lack of reliable, insulin-sensitive, human, in vitro, hepatic models. Here, we report human skin stem cell-derived hepatic cells (hSKP-HPC) as a unique in vitro model to study insulin-driven DNL (iDNL), evidenced by both gene expression and lipid accumulation readouts. Insulin-sensitive hSKP-HPC showed increased sterol regulatory element-binding protein 1c (SREBP-1c) expression, a key transcription factor for DNL. Furthermore, this physiologically relevant in vitro human steatosis model allowed both inhibition and activation of the iDNL pathway using reference inhibitors and activators, respectively. Optimisation of the lipid accumulation assay to a high-throughput, 384-well format enabled the screening of a library of annotated compounds, delivering new insights on key players in the iDNL pathway and MASLD pathophysiology. Together, these results establish the value of the hSKP-HPC model in preclinical development of antisteatotic drugs to combat MASLD.
Competing Interests: Declaration of competing interest M. Vrints, T. Van Eeckhoutte, M. Jans, J. Van Der Schueren and F. Beirinckx are employed at Galapagos NV. K. Buyl, R. Fernando, T. Desmae, J. Boeckmans, R. M. Rodrigues, V. De Boe, V. Rogiers, J. De Kock and T. Vanhaecke declare no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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