The activation of M (3) muscarinic receptor reverses liver injuryvia the Sp1/lncRNA Gm2199/miR-212 axis.
The activation of M (3) muscarinic receptor reverses liver injuryvia the Sp1/lncRNA Gm2199/miR-212 axis.
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DOI：
10.3724/abbs.2022119
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发表时间：
2022-09-25
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Zhang H;Gao Y;Liu B;Jin H;Fan L;Yang X;Gao Q;Yu Y;Guo Y;Liu Y
乙酰胆碱受体(MRS)在肝纤维化的调节中起重要作用，受体激动剂和拮抗剂均可影响肝细胞增殖。然而，对M3R亚型和相关信号通路在肝损伤中的影响知之甚少。本研究旨在探讨M3R在肝损伤调节中的作用及其机制。观察给予M3R激动剂后肝损伤程度及相关指标丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、羟脯氨酸(HYP)、转化生长因子-β1(TGFR-β1)的变化。Western印迹分析和qRT-PCR分析表明，转录因子Sp1和长非编码RNA(LncRNA)Gm2199也发生了显著变化。挽救实验进一步证实M3R通过调节Sp1和Gm2199促进肝细胞增殖。活化的M3R可以通过抑制Sp1的表达来特异性地调节Gm2199。同时，Gm2199直接调控miR-212，ERK是miR-212的潜在靶点。总之，这些发现定义了一种激活M3R以逆转肝损伤的新机制，该机制通过Sp1/GM2199/miR-212/ERK轴影响肝细胞增殖。
Muscarinic acetylcholine receptors (MRs) play important roles in the regulation of hepatic fibrosis and the receptor agonists and antagonists can affect hepatocyte proliferation. However, little is known about the impact of M 3R subtypes and associated signaling pathways on liver injury. The aim of this study is to explore the function and mechanism of M 3R in the regulation of liver injury. We evaluate liver injury and detect the changes in related indexes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline (HYP), and transforming growth factor-β1 (TGF-β1), after administration of an M 3R agonist. Western blot analysis and qRT-PCR show that the transcription factor Sp1 and long noncoding RNA (lncRNA) Gm2199 are also changed significantly. Rescue assay is performed to further confirm that M 3R contributes to the progression of hepatocyte proliferation through regulating Sp1 and Gm2199. The activated M 3R can specifically regulate Gm2199 by inhibiting the expression of Sp1. Meanwhile, Gm2199 directly regulates miR-212, and ERK is a potential target of miR-212. Collectively, these findings define a novel mechanism for activating M 3R to reverse liver injury, which affects hepatocyte proliferation through the Sp1/Gm 2199/miR-212/ERK axis.
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