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Interleukin-22 ameliorates neutrophil-driven nonalcoholic steatohepatitis through multiple targets.
Interleukin-22 通过多个靶点改善中性粒细胞驱动的非酒精性脂肪性肝炎。
Inflammation extracellular vesicles mitochondrial DNA oxidative stress
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摘要

Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C-X-C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high-fat diet (HFD)-fed mice. Here we demonstrate that overexpression of Cxcl1 in the liver alone promotes steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as ASK1 and p38MAPK) activation. Myeloid cell-specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1-induced NASH and stress kinase activation in HFD-fed mice. Treatment with interleukin (IL)-22, a cytokine with multiple targets, ameliorated CXCL1/HFD-induced NASH or methionine-choline deficient diet-induced NASH in mice. Mechanistically, IL-22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL-22 treatment attenuated the inflammatory functions of hepatocyte-derived, mitochondrial DNA-enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. CONCLUSION: Hepatic overexpression of CXCL1 is sufficient to drive steatosis-to-NASH progression in HFD-fed mice through neutrophil-derived reactive oxygen species and activation of stress kinases, which can be reversed by IL-22 treatment via the induction of metallothionein.

译文

非酒精性脂肪性肝病包括一系列疾病,从单纯脂肪变性到非酒精性脂肪性肝炎 (NASH) 、肝硬化和肝癌。目前,简单的脂肪变性如何发展为 NASH 仍然不清楚,并且缺乏有效的药物治疗。C-X-C 基序趋化因子配体 1 (CXCL1) 的肝脏表达,CXCL1 是中性粒细胞浸润的关键趋化因子 (NASH 的标志), 在 NASH 患者中高度升高,但在肥胖个体或高脂饮食 (HFD) 喂养的小鼠中不升高。在这里,我们证明了在单独的肝脏中 Cxcl1 的过表达通过诱导中性粒细胞浸润、氧化应激促进 HFD 喂养小鼠的脂肪变性到 NASH 的进展, 和应激激酶 (如 ASK1 和 p38MAPK) 的激活。中性粒细胞胞质因子 1 (Ncf1)/p47phox 基因的髓系细胞特异性缺失,该基因编码了介导中性粒细胞氧化爆发的 NADPH 氧化酶 2 复合物的一个组成部分, 显著降低 HFD 喂养小鼠 CXCL1-induced NASH 和应激激酶活化。用白细胞介素 (IL)-22 (一种具有多靶点的细胞因子) 治疗,可改善小鼠 CXCL1/HFD 诱导的 NASH 或蛋氨酸-胆碱缺乏饮食诱导的 NASH。从机制上来说,IL-22 通过诱导金属硫蛋白 (一种最有效的抗氧化蛋白) 来阻断肝脏氧化应激及其相关的应激激酶。此外,尽管它不针对免疫细胞,但 IL-22 治疗减弱了肝细胞来源、线粒体 DNA 富集的胞外囊泡的炎症功能,从而抑制了 NASH 中的肝脏炎症。结论: 肝 CXCL1 的过表达足以通过中性粒细胞来源的活性氧和应激激酶的激活,在 HFD 喂养的小鼠中驱动脂肪变性向 NASH 的进展, 它可以通过诱导金属硫蛋白的 IL-22 处理来逆转。

Nonalcoholic Steatohepatitis

消化 炎症 疾病
概述  :  

非酒精性脂肪性肝炎(nonalcoholic steatohepatitis ,NASH)又称代谢性脂肪性肝炎,是一种以脂肪在肝脏中过量蓄积为主要特征的慢性肝病,与酒精性肝病类似,但发生在不喝酒或者少喝酒的人身上,日常生活中摄入过量脂肪也可能发病,并有较高风险发展成肝硬化和肝癌。非酒精性脂肪性肝炎与肥胖、胰岛素抵抗、Ⅱ型糖尿病、高脂血症等代谢紊乱关系密切,其主要特征为肝细胞损伤、肝脏炎症、进行性纤维化,已经成为了肝衰竭和肝细胞癌的最重要原因。 病因和发病机制NA

nonalcoholic 英 [,nɒnælkə'hɒlɪk] 美 [,nɑn,ælkə'hɑlɪk]

释义   adj. 不含酒精的

例句   Insulin resistance, diabetes and high levels of cholesterol all contribute to the development of nonalcoholic fatty liver disease and its complications. 胰岛素抵抗、糖尿病及高水平的胆固醇均导致非酒精性脂肪肝的发展及并发症的产生。

 

steatohepatitis 英 [,stiə'to ˌhepəˈtaɪtɪs] 美 [,stiə'to ˌhɛpəˈtaɪtɪs]

释义   n. 脂肪性肝炎

例句   To explore the risk factors of non-alcoholic steatohepatitis(NASH) in children. 探讨儿童非酒精性脂肪性肝炎(NASH)的危险因素。


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