한빛사논문
- 조회280
Yun Kwon 1,2,3,6, Pascal Gottmann 2,4, Surui Wang 1,2,6, Joel Tissink 1,2,6, Karsten Motzler 1,2,6, Revathi Sekar 1,2,6, Wiebke Albrecht 5, Cristina Cadenas 5, Jan G. Hengstler 5, Annette Schürmann 2,4, Anja Zeigerer 1,2,3,6
1Institute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany
2German Center for Diabetes Research (DZD), Neuherberg, Germany
3European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
4Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany
5Leibniz Research Centre for Working Environment and Human Factors (IfADo), Department of Toxicology, Dortmund, Germany
6Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
Corresponding author: Anja Zeigerer
Abstract
Background & aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease. Its limited treatment options warrant novel pre-clinical models for target selection and drug validation. We have established and extensively characterized a primary human steatotic hepatocyte in vitro model system that could guide treatment strategies for MASLD.
Methods: Cryopreserved primary human hepatocytes from five donors varying in sex and ethnicity were cultured with free fatty acids (FFA) in 3D collagen sandwich for 7 days and the development of MASLD was followed by assessing classical hepatocellular functions. As proof of concept, the effects of the drug Firsocostat (GS-0976) on in vitro MASLD phenotypes were evaluated.
Results: Incubation with FFA induced steatosis, insulin resistance, mitochondrial dysfunction, inflammation, and alterations in prominent human gene signatures similar to patients with MASLD, indicating the recapitulation of human MASLD in this system. As the application of Firsocostat rescued clinically observed fatty liver disease pathologies, it highlights the ability of the in vitro system to test drug efficacy and potentially characterize their mode of action.
Conclusions: Altogether, our human MASLD in vitro model system could guide the development and validation of novel targets and drugs for the treatment of MASLD.
Impact and implications: Due to low drug efficacy and high toxicity, a clinical treatment option for MASLD is limited. To facilitate earlier stop-go decisions in drug development, we have established a primary human steatotic hepatocyte in vitro model. As the model recapitulates clinically relevant MASLD characteristics at high phenotypic resolution, it can serve as a pre-screening platform and guide target identification and validation in MASLD therapy.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-19)
- 국외 연구진
- 생명과학 > 세포생물학
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