Kwon Yun, Gottmann Pascal, Wang Surui, Tissink Joel, Motzler Karsten, Sekar Revathi, Albrecht Wiebke, Cadenas Cristina, Hengstler Jan G, Schürmann Annette, Zeigerer Anja
Institute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany, Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany; German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Nuthetal, Germany.
J Hepatol. 2025 Jan;82(1):18-27. doi: 10.1016/j.jhep.2024.06.040. Epub 2024 Jul 6.
BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease. Owing to limited available treatment options, novel pre-clinical models for target selection and drug validation are warranted. We have established and extensively characterized a primary human steatotic hepatocyte in vitro model system that could guide the development of treatment strategies for MASLD.
Cryopreserved primary human hepatocytes from five donors varying in sex and ethnicity were cultured with free fatty acids in a 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.
Incubation with free fatty acids 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. The application of firsocostat rescued clinically observed fatty liver disease pathologies, highlighting the ability of the in vitro system to test the efficacy and potentially characterize the mode of action of drug candidates.
Altogether, our human MASLD in vitro model system could guide the development and validation of novel targets and drugs for the treatment of MASLD.
Due to low drug efficacy and high toxicity, clinical treatment options for metabolic dysfunction-associated steatotic liver disease (MASLD) are currently 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.
代谢功能障碍相关脂肪性肝病（MASLD）是慢性肝病最常见的病因。由于可用的治疗选择有限，因此需要用于靶点选择和药物验证的新型临床前模型。我们已经建立并广泛表征了一种体外原发性人类脂肪变性肝细胞模型系统，该系统可指导MASLD治疗策略的开发。
将来自五名不同性别和种族供体的冷冻保存的原发性人类肝细胞与游离脂肪酸在3D胶原三明治中培养7天，并通过评估经典肝细胞功能来跟踪MASLD的发展。作为概念验证，评估了药物非索考司他（GS-0976）对体外MASLD表型的影响。
与游离脂肪酸孵育会诱导脂肪变性、胰岛素抵抗、线粒体功能障碍、炎症以及与MASLD患者相似的突出人类基因特征改变，表明该系统中重现了人类MASLD。非索考司他的应用挽救了临床上观察到的脂肪性肝病病理，突出了该体外系统测试候选药物疗效并潜在表征其作用方式的能力。
总之，我们的人类MASLD体外模型系统可指导用于治疗MASLD的新型靶点和药物的开发与验证。
由于药物疗效低和毒性高，代谢功能障碍相关脂肪性肝病（MASLD）的临床治疗选择目前有限。为了促进药物开发中更早的“继续-停止”决策，我们建立了一种原发性人类脂肪变性肝细胞体外模型。由于该模型在高表型分辨率下重现了临床相关的MASLD特征，它可以作为一个预筛选平台，并指导MASLD治疗中的靶点识别和验证。
