Metabolic Dysfunction-Associated Steatotic Liver Disease in a Dish: Human Precision-Cut Liver Slices as a Platform for Drug Screening and Interventions

• Published in: Nutrients Vol. 16; no. 5; p. 626
• Main Authors: Li, Mei, Larsen, Frederik T, van den Heuvel, Marius C, Gier, Konstanze, Gorter, Alan R, Oosterhuis, Dorenda, Bijzet, Johan, de Meijer, Vincent E, Ravnskjaer, Kim, Nagelkerke, Anika, Olinga, Peter
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23-02-2024; MDPI
• Subjects: Adenosine triphosphate; B cells; Blood & organ donations; Caustic soda; Drug Evaluation, Preclinical; Fatty acids; Fatty Liver; Gene expression; Genes; Glucose; Health aspects; hepatic steatosis; Humans; Inflammation; Lipids; Liver diseases; liver fibrosis; long-term incubation; Medical screening; Metabolic Diseases; metabolic dysfunction-associated steatotic liver disease (MASLD); Metabolism; non-alcoholic fatty liver disease (NAFLD); Physiological aspects; precision-cut liver slices (PCLSs); Proteins; R&D; Research & development; RNA; RNA sequencing; Tissue Inhibitor of Metalloproteinase-1; Transforming growth factors; Type 2 diabetes; Netherlands; United States > US; Germany; non-alcoholic fatty liver disease (NAFLD); liver fibrosis; long-term incubation; metabolic dysfunction-associated steatotic liver disease (MASLD); precision-cut liver slices (PCLSs); hepatic steatosis
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu16050626

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing healthcare problem with limited therapeutic options. Progress in this field depends on the availability of reliable preclinical models. Human precision-cut liver slices (PCLSs) have been employed to replicate the initiation of MASLD, but a comprehensive investigation into MASLD progression is still missing. This study aimed to extend the current incubation time of human PCLSs to examine different stages in MASLD. Healthy human PCLSs were cultured for up to 96 h in a medium enriched with high sugar, high insulin, and high fatty acids to induce MASLD. PCLSs displayed hepatic steatosis, characterized by accumulated intracellular fat. The development of hepatic steatosis appeared to involve a time-dependent impact on lipid metabolism, with an initial increase in fatty acid uptake and storage, and a subsequent down-regulation of lipid oxidation and secretion. PCLSs also demonstrated liver inflammation, including increased pro-inflammatory gene expression and cytokine production. Additionally, liver fibrosis was also observed through the elevated production of pro-collagen 1a1 and tissue inhibitor of metalloproteinase-1 (TIMP1). RNA sequencing showed that the tumor necrosis factor alpha (TNFα) signaling pathway and transforming growth factor beta (TGFβ) signaling pathway were consistently activated, potentially contributing to the development of inflammation and fibrosis. In conclusion, the prolonged incubation of human PCLSs can establish a robust ex vivo model for MASLD, facilitating the identification and evaluation of potential therapeutic interventions.