Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China.
Fibrosis Research Program, Division of Pulmonary and Critical Care Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Int J Mol Sci. 2023 Jul 11;24(14):11313. doi: 10.3390/ijms241411313.
Chronic liver diseases affect over a billion people worldwide and often lead to fibrosis. Nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes, is characterized by liver fibrosis, and its pathogenesis remains largely unknown, with no effective treatment available. Necroptosis has been implicated in liver fibrosis pathogenesis. However, there is a lack of research on necroptosis specific to certain cell types, particularly the vascular system, in the context of liver fibrosis and NASH. Here, we employed a mouse model of NASH in combination with inducible gene knockout mice to investigate the role of endothelial necroptosis in NASH progression. We found that endothelial cell (EC)-specific knockout of mixed lineage kinase domain-like protein (MLKL), a critical executioner involved in the disruption of cell membranes during necroptosis, alleviated liver fibrosis in the mouse NASH model. Mechanistically, EC-specific deletion of mitigated the activation of TGFβ/Smad 2/3 pathway, disrupting the pro-fibrotic crosstalk between endothelial cells and hepatic stellate cells (HSCs). Our findings highlight endothelial MLKL as a promising molecular target for developing therapeutic interventions for NASH.
慢性肝脏疾病影响着全球超过 10 亿人，常常导致纤维化。非酒精性脂肪性肝炎（NASH）是一种与代谢综合征在全球范围内急剧增加相平行的疾病，其特征是肝纤维化，但其发病机制在很大程度上仍然未知，并且尚无有效的治疗方法。细胞坏死已被牵涉到肝纤维化的发病机制中。然而，在肝纤维化和 NASH 的背景下，针对特定细胞类型（特别是血管系统）的细胞坏死的研究还很缺乏。在这里，我们结合诱导型基因敲除小鼠，使用 NASH 小鼠模型，研究内皮细胞坏死在 NASH 进展中的作用。我们发现，混合谱系激酶结构域样蛋白（MLKL）是参与细胞坏死时破坏细胞膜的关键执行者，内皮细胞特异性敲除 MLKL 可减轻 NASH 小鼠模型中的肝纤维化。在机制上，内皮细胞特异性缺失减轻了 TGFβ/Smad 2/3 通路的激活，破坏了内皮细胞和肝星状细胞（HSCs）之间的促纤维化串扰。我们的研究结果突出了内皮细胞 MLKL 作为开发 NASH 治疗干预措施的有希望的分子靶点。
