The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression.
The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression.
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DOI：
10.1038/s41467-021-27539-3
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发表时间：
2021-12-10
影响因子：
16.6
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Li X;Yuan B;Lu M;Wang Y;Ding N;Liu C;Gao M;Yao Z;Zhang S;Zhao Y;Xie L;Chen Z
非酒精性脂肪性肝炎（NASH）是非酒精性脂肪肝（NAFL）进展为肝硬化的关键步骤。然而，NAFL 向 NASH 转变的分子机制在很大程度上尚不清楚。在这里，我们将甲基转移酶样 3 (METTL3) 确定为 NASH 发病机制的关键负调节因子。肝细胞特异性删除 Mettl3，通过增加 CD36 介导的肝脏游离脂肪酸摄取和 CCL2 诱导的炎症来驱动 NAFL 至 NASH 的进展，这是由于 Cd36 和 Ccl2 启动子区域染色质可及性增加所致。 CD36 和 CCL2 的抗体阻断可改善肝脏 Mettl3 敲除小鼠的 NASH 进展。 Mettl3 的肝脏过度表达通过抑制 CD36 和 CCL2 的表达来防止 NASH 进展。从机制上讲，METTL3 直接与 Cd36 和 Ccl2 基因的启动子结合，并招募 HDAC1/2 诱导其启动子中的 H3K9 和 H3K27 脱乙酰化，从而抑制 Cd36 和 Ccl2 转录。此外，METTL3 在 NASH 中从细胞核易位至细胞质，这与 CDK9 介导的 METTL3 磷酸化有关。我们的数据揭示了 METTL3 通过组蛋白修饰途径负向调节肝脏 Cd36 和 Ccl2 基因转录以防止 NASH 进展的机制。非酒精性脂肪肝发展为更严重的非酒精性脂肪性肝炎的机制尚不完全清楚。作者在此表明 METTL3（一种催化 mRNA m6 修饰的 RNA 甲基转移酶）通过抑制 Cd36 和 Ccl2 的转录来负向调节 NASH 进展。
Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of Mettl3 drives NAFL-to-NASH progression by increasing CD36-mediated hepatic free fatty acid uptake and CCL2-induced inflammation, which is due to increased chromatin accessibility in the promoter region of Cd36 and Ccl2. Antibody blockade of CD36 and CCL2 ameliorates NASH progression in hepatic Mettl3 knockout mice. Hepatic overexpression of Mettl3 protects against NASH progression by inhibiting the expression of CD36 and CCL2. Mechanistically, METTL3 directly binds to the promoters of the Cd36 and Ccl2 genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing Cd36 and Ccl2 transcription. Furthermore, METTL3 is translocated from the nucleus to the cytosol in NASH, which is associated with CDK9-mediated phosphorylation of METTL3. Our data reveal a mechanism by which METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against NASH progression. Mechanisms that underlie the progression of non-alcoholic fatty liver disease to the more severe non-alcoholic steatohepatitis are incompletely understood. Here the authors show that METTL3, a RNA methyltransferase that catalyzes mRNA m6 modifications, negatively regulates NASH progression via inhibiting the transcription of Cd36 and Ccl2.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
23.9
作者：
Batista, Pedro J.;Molinie, Benoit;Wang, Jinkai;Qu, Kun;Zhang, Jiajing;Li, Lingjie;Bouley, Donna M.;Lujan, Ernesto;Haddad, Bahareh;Daneshvar, Kaveh;Carter, Ava C.;Flynn, Ryan A.;Zhou, Chan;Lim, Kok-Seong;Dedon, Peter;Wernig, Marius;Mullen, Alan C.;Xing, Yi;Giallourakis, Cosmas C.;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
DOI：
10.1126/science.aau1646
发表时间：
2018-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Frye M;Harada BT;Behm M;He C
通讯作者：
He C
影响因子：
3.7
作者：
Lefebvre E;Moyle G;Reshef R;Richman LP;Thompson M;Hong F;Chou HL;Hashiguchi T;Plato C;Poulin D;Richards T;Yoneyama H;Jenkins H;Wolfgang G;Friedman SL
通讯作者：
Friedman SL
影响因子：
24.5
作者：
Baeck, Christer;Wehr, Alexander;Tacke, Frank
通讯作者：
Tacke, Frank