Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Int Immunopharmacol. 2022 Dec;113(Pt A):109229. doi: 10.1016/j.intimp.2022.109229. Epub 2022 Oct 30.
CD73 is a membrane-bound glycoprotein that can dephosphorylate AMP to adenosine. Increasing evidence has shown that CD73 is involved in the occurrence and development of liver fibrosis. However, the potential mechanism by which CD73 affects the progression of alcohol-related liver fibrosis (ALF) remains unknown. This study aimed to examine the role and mechanism of CD73 in autophagy in HSC-T6 cells and its role in ALF in mice that treated with alcohol plus CCl. We found that CD73 knockout reduced serum alanine aminotransferase and aspartate aminotransferase levels and decreased liver injury and collagen deposition. Furthermore, autophagy-related indicators were downregulated in the liver fibrosis tissues of CD73 (EtOH + CCl4) mice. In vitro, the expression of CD73 and autophagy increased in activated HSC-T6 cells. Autophagy inhibitor, 3-methyladenine, reduced autophagy and activation of acetaldehyde-induced HSC-T6 cells. When using CD73-siRNA, autophagy in HSC-T6 cells was found to be downregulated. However, the CD73 plasmid increased the activation and autophagy of hepatic stellate cells (HSCs). In addition, CD73 induced autophagy through the AMPK/AKT/mTOR pathway, which is characterized by an increase in the ratio of P-AMPKα/AMPKα and a decrease in the ratio of P-AKT/AKT and P-mTOR/mTOR. Our study found that CD73 promotes HSCs activation by regulating autophagy through the AMPK/AKT/mTOR signaling pathway.
CD73 是一种膜结合糖蛋白，可将 AMP 去磷酸化为腺苷。越来越多的证据表明，CD73 参与了肝纤维化的发生和发展。然而，CD73 影响酒精相关肝纤维化（ALF）进展的潜在机制尚不清楚。本研究旨在研究 CD73 在 HSC-T6 细胞自噬中的作用及其在酒精加 CCl 处理的小鼠 ALF 中的作用。我们发现，CD73 敲除可降低血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平，并减少肝损伤和胶原沉积。此外，CD73（EtOH+CCl4）小鼠肝纤维化组织中的自噬相关指标下调。在体外，激活的 HSC-T6 细胞中 CD73 和自噬表达增加。自噬抑制剂 3-甲基腺嘌呤可降低乙醛诱导的 HSC-T6 细胞的自噬和激活。当使用 CD73-siRNA 时，发现 HSC-T6 细胞中的自噬减少。然而，CD73 质粒增加了肝星状细胞（HSCs）的激活和自噬。此外，CD73 通过 AMPK/AKT/mTOR 通路诱导自噬，其特征是 P-AMPKα/AMPKα 比值增加，P-AKT/AKT 和 P-mTOR/mTOR 比值降低。我们的研究发现，CD73 通过 AMPK/AKT/mTOR 信号通路调节自噬，促进 HSCs 的激活。
