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<p>Metabolic dysfunction-associated steatohepatitis (MASH) represents a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), largely due to metabolic dysregulation and sustained liver inflammation. TNF-α plays a pivotal role in MASH pathogenesis by inducing cell death, inflammation, and decreased insulin sensitivity. In this study we investigated the effects of TNF-α in human precision-cut liver slices (PCLS) under healthy or steatotic conditions, to provide insights into MASH pathogenesis. PCLS were prepared from human liver tissue and cultured in control (WEGG) and hyper-nutritive (GFIPO) mediums with or without TNF-α (50 ng/mL) for 96&#xa0;h. Viability was assessed via ATP content, lipid accumulation by triglyceride (TG) assay, and transcriptomic changes through Next-Generation Sequencing. The protein levels of cytokines, chemokines, and fibrotic mediators released from PCLS were quantified using Luminex assay and ELISA. TNF-α significantly altered the transcriptional profiles in PCLS, inducing pro-inflammatory and pro-fibrotic signaling, and downregulating lipid metabolic processes in both WEGG and GFIPO media. TNF-α showed a trend in elevating intracellular TG in both conditions, albeit not statistically significant. On protein levels, TNF-α supplementation to WEGG medium induced the expression of IL8, CCL2, CCL19, PDGF-AB/BB, TGF-α, and MMP9. GFIPO medium alone induced inflammatory and fibrotic responses indicated by elevated levels of IL8, CCL2, and Pro-collagen 1A1. GFIPO medium with TNF-α supplementation further exacerbated the inflammatory and fibrotic responses, characterized by increased release of cytokines and growth factors. This human PCLS model effectively demonstrated the co-occurrence of key features of MASH, such as steatosis, inflammation, and fibrosis, highlighting the impact of metabolic stress and inflammatory cytokine TNF-α on these disease characteristics, and the potential of the PCLS model in exploring mechanism of MASH progression.</p>

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Effects of TNF-α in Human Precision-Cut Liver Slices and its Implications for Metabolic Dysfunction-Associated Steatohepatitis Progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Ke Luo,
  • Mei Li,
  • Alan R. Gorter,
  • Dorenda Oosterhuis,
  • Vincent E. de Meijer,
  • Peter Olinga

摘要

Metabolic dysfunction-associated steatohepatitis (MASH) represents a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), largely due to metabolic dysregulation and sustained liver inflammation. TNF-α plays a pivotal role in MASH pathogenesis by inducing cell death, inflammation, and decreased insulin sensitivity. In this study we investigated the effects of TNF-α in human precision-cut liver slices (PCLS) under healthy or steatotic conditions, to provide insights into MASH pathogenesis. PCLS were prepared from human liver tissue and cultured in control (WEGG) and hyper-nutritive (GFIPO) mediums with or without TNF-α (50 ng/mL) for 96 h. Viability was assessed via ATP content, lipid accumulation by triglyceride (TG) assay, and transcriptomic changes through Next-Generation Sequencing. The protein levels of cytokines, chemokines, and fibrotic mediators released from PCLS were quantified using Luminex assay and ELISA. TNF-α significantly altered the transcriptional profiles in PCLS, inducing pro-inflammatory and pro-fibrotic signaling, and downregulating lipid metabolic processes in both WEGG and GFIPO media. TNF-α showed a trend in elevating intracellular TG in both conditions, albeit not statistically significant. On protein levels, TNF-α supplementation to WEGG medium induced the expression of IL8, CCL2, CCL19, PDGF-AB/BB, TGF-α, and MMP9. GFIPO medium alone induced inflammatory and fibrotic responses indicated by elevated levels of IL8, CCL2, and Pro-collagen 1A1. GFIPO medium with TNF-α supplementation further exacerbated the inflammatory and fibrotic responses, characterized by increased release of cytokines and growth factors. This human PCLS model effectively demonstrated the co-occurrence of key features of MASH, such as steatosis, inflammation, and fibrosis, highlighting the impact of metabolic stress and inflammatory cytokine TNF-α on these disease characteristics, and the potential of the PCLS model in exploring mechanism of MASH progression.