下调和上调
CX3CR1型
癌症研究
脂肪性肝炎
纤维化
脂肪肝
生物
肝纤维化
肝星状细胞
CCR2型
信号转导
脂肪变性
单核细胞
趋化因子
细胞生物学
炎症
免疫学
趋化因子受体
医学
内分泌学
病理
生物化学
疾病
基因
作者
Yue-fan Wang,Wenli Zhang,Zhi-xuan Li,Yue Liu,Jian Tan,Hao-zan Yin,Zhichao Zhang,Xian-jie Piao,Min-hao Ruan,Zhihui Dai,Sijie Wang,Chen-yang Mu,Ji‐hang Yuan,Shuhan Sun,Hui Liu,Fu Yang
标识
DOI:10.1038/s41392-024-01797-1
摘要
Abstract Without intervention, a considerable proportion of patients with metabolism‐associated fatty liver disease (MAFLD) will progress from simple steatosis to metabolism‐associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma. However, the molecular mechanisms that control progressive MAFLD have yet to be fully determined. Here, we unraveled that the expression of the N6-methyladenosine (m6A) methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD, whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation, liver injury, and fibrosis. Conversely, hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet (HFD). Notably, in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner, which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1 + Ccr2 + monocyte-derived macrophages (Mo-macs). In detail, Cx3cr1 + Ccr2 + Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells (HSCs) to promote liver fibrosis. Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1 + Ccr2 + Mo-macs. Restoration of METTL14 or GLS2, or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis. Taken together, these findings indicate potential therapies for the treatment of MAFLD progression.
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