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Metabolic Dysfunction-Associated Steatotic Liver Disease in a Dish: Human Precision-Cut Liver Slices as a Platform
Mei Li1, Frederik T Larsen2, Marius C van den Heuvel3
1Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands.
Abstract:
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.
Insights
Extended incubation of human liver slices models metabolic dysfunction-associated steatotic liver disease (MASLD) progression, including steatosis, inflammation, and fibrosis. This offers a new preclinical tool for developing MASLD therapies.
Area of Science:
- Hepatology and metabolic research
- Preclinical disease modeling
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant health concern with limited treatment options.
- Reliable preclinical models are crucial for advancing MASLD research and therapy development.
- Existing human precision-cut liver slice (PCLS) models primarily focus on MASLD initiation, lacking comprehensive progression studies.
Purpose of the Study:
- To extend the incubation period of human PCLSs to investigate MASLD progression.
- To establish a robust ex vivo model for evaluating potential MASLD therapeutic interventions.
Main Methods:
- Healthy human PCLSs were cultured for up to 96 hours.
- A specialized medium containing high sugar, high insulin, and high fatty acids was used to induce MASLD.
- Analysis included assessment of steatosis, inflammation, fibrosis markers, and gene expression via RNA sequencing.
Main Results:
- PCLSs developed hepatic steatosis with time-dependent alterations in lipid metabolism (increased uptake/storage, decreased oxidation/secretion).
- MASLD induction led to liver inflammation (elevated pro-inflammatory genes and cytokines) and fibrosis (increased pro-collagen 1a1 and TIMP1).
- RNA sequencing revealed consistent activation of TNFα and TGFβ signaling pathways, implicated in inflammation and fibrosis.
Conclusions:
- Prolonged incubation of human PCLSs effectively models MASLD progression, encompassing steatosis, inflammation, and fibrosis.
- This extended PCLS model provides a valuable platform for identifying and testing novel MASLD therapeutic strategies.
- The study highlights the utility of PCLSs for comprehensive ex vivo investigation of liver diseases.
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