Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000, Rennes, France.
Department of Clinical Sciences, College of Veterinary and Animal Sciences, University of Veterinary and Animal Sciences, Jhang, Lahore, Pakistan.
J Mol Med (Berl). 2022 Jul;100(7):1027-1038. doi: 10.1007/s00109-022-02192-5. Epub 2022 Apr 27.
Non-alcoholic steatohepatitis (NASH), a chronic liver disease that emerged in industrialized countries, can further progress into liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the next decade, NASH is predicted to become the leading cause of liver transplantation, the only current interventional therapeutic option. Hepatocyte death, triggered by different death ligands, plays key role in its progression. Previously, we showed that the receptor-interacting protein kinase-1 (RIPK1) in hepatocytes exhibits a protective role in ligand-induced death. Now, to decipher the role of RIPK1 in NASH, Ripk1 mice, deficient for RIPK1 only in liver parenchymal cells, and their wild-type littermates (Ripk1) were fed for 3, 5, or 12 weeks with high-fat high-cholesterol diet (HFHCD). The main clinical signs of NASH were analyzed to compare the pathophysiological state established in mice. Most of the symptoms evolved similarly whatever the genotype, whether it was the increase in liver to body weight ratio, the steatosis grade or the worsening of liver damage revealed by serum transaminase levels. In parallel, inflammation markers followed the same kinetics with significant equivalent inductions of cytokines (hepatic mRNA levels and blood cytokine concentrations) and a main peak of hepatic infiltration of immune cells at 3 weeks of HFHCD. Despite this identical inflammatory response, more hepatic fibrosis was significantly evidenced at week 12 in Ripk1 mice. This coincided with over-induced rates of transcripts of genes implied in fibrosis development (Tgfb1, Tgfbi, Timp1, and Timp2) in Ripk1 animals. In conclusion, our results show that RIPK1 in hepatocyte limits the progression of liver fibrosis during NASH.
非酒精性脂肪性肝炎（NASH）是一种在工业化国家出现的慢性肝病，可进一步发展为肝纤维化、肝硬化和肝细胞癌。预计在未来十年内，NASH 将成为肝移植的主要原因，而肝移植是目前唯一的介入治疗选择。不同死亡配体触发的肝细胞死亡在其进展中起着关键作用。此前，我们表明肝细胞中的受体相互作用蛋白激酶-1（RIPK1）在配体诱导的死亡中表现出保护作用。现在，为了解 RIPK1 在 NASH 中的作用，我们使用缺乏 RIPK1 仅在肝实质细胞中的 Ripk1 小鼠及其野生型同窝仔鼠（Ripk1）喂食高脂肪高胆固醇饮食（HFHCD）3、5 或 12 周。分析了 NASH 的主要临床症状，以比较在小鼠中建立的病理生理状态。无论基因型如何，大多数症状的演变都相似，无论是肝重与体重比的增加、脂肪变性程度还是血清转氨酶水平揭示的肝损伤恶化。平行地，炎症标志物遵循相同的动力学，细胞因子的肝 mRNA 水平和血液细胞因子浓度）和免疫细胞在 HFHCD 第 3 周时对肝脏的主要浸润均有显著的等同诱导。尽管存在相同的炎症反应，但在 Ripk1 小鼠中，在第 12 周时明显有更多的肝纤维化。这与 Ripk1 动物中纤维化发展相关基因（Tgfb1、Tgfbi、Timp1 和 Timp2）的转录物过度诱导相一致。总之，我们的研究结果表明，肝细胞中的 RIPK1 限制了 NASH 期间肝纤维化的进展。
