Arginine Methylation of Integrin Alpha-4 Prevents Fibrosis Development in Alcohol-Associated Liver Disease.
Arginine Methylation of Integrin Alpha-4 Prevents Fibrosis Development in Alcohol-Associated Liver Disease.
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DOI：
10.1016/j.jcmgh.2022.09.013
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发表时间：
2023
影响因子：
7.2
通讯作者：
Tikhanovich, Irina
中科院分区：
文献类型：
--
作者：
Schonfeld, Michael;Villar, Maria T.;Artigues, Antonio;Weinman, Steven A.;Tikhanovich, Irina
酒精相关性肝病（ALD）包括一系列疾病，包括脂肪变性、脂肪性肝炎、纤维化和肝硬化。我们的目的是研究蛋白质精氨酸甲基转移酶6（PRMT 6），一种新的肝功能调节剂，在ALD进展中的作用。Prmt 6缺陷型小鼠和野生型同窝出生的小鼠被喂食饮用水中含有酒精的西方饮食16周。将喂食标准普通饲料或单独西方饲料的小鼠用作对照。我们发现PRMT 6在肝脏中的表达在2种ALD模型中下调，并且与小鼠和人肝脏标本中的疾病严重程度呈负相关。prmt 6缺陷小鼠1年后自发发生肝纤维化，高脂饮食喂养或硫代乙酰胺治疗后发生更严重的纤维化。在酒精存在的情况下，Prmt 6缺乏会导致纤维化发展急剧增加，但不影响脂质积聚或肝损伤。在肝脏中，PRMT 6主要在巨噬细胞和内皮细胞中表达。在Prmt 6敲除小鼠中用野生型巨噬细胞瞬时替换敲除巨噬细胞减少了促纤维化信号传导并阻止了纤维化进展。我们发现PRMT 6通过R464残基处的整合素α-4的甲基化来降低肝巨噬细胞中的促纤维化信号传导。整合素α-4主要在浸润的单核细胞衍生的巨噬细胞中表达。用CCR 2抑制剂阻断单核细胞向肝脏的浸润减少了基因敲除小鼠的纤维化发展，并消除了基因型之间的差异。综上所述，我们的数据表明，酒精介导的Prmt 6丢失通过减少整合素甲基化和增加巨噬细胞中的促纤维化信号传导而促进酒精相关的纤维化发展。
Alcohol-associated liver disease (ALD) comprises a spectrum of disorders including steatosis, steatohepatitis, fibrosis, and cirrhosis. We aimed to study the role of protein arginine methyltransferase 6 (PRMT6), a new regulator of liver function, in ALD progression. Prmt6-deficient mice and wild-type littermates were fed Western diet with alcohol in the drinking water for 16 weeks. Mice fed standard chow diet or Western diet alone were used as a control. We found that PRMT6 expression in the liver is down-regulated in 2 models of ALD and negatively correlates with disease severity in mice and human liver specimens. Prmt6-deficient mice spontaneously developed liver fibrosis after 1 year and more advanced fibrosis after high-fat diet feeding or thioacetamide treatment. In the presence of alcohol Prmt6 deficiency resulted in a dramatic increase in fibrosis development but did not affect lipid accumulation or liver injury. In the liver PRMT6 is primarily expressed in macrophages and endothelial cells. Transient replacement of knockout macrophages with wild-type macrophages in Prmt6 knockout mice reduced profibrotic signaling and prevented fibrosis progression. We found that PRMT6 decreases profibrotic signaling in liver macrophages via methylation of integrin α-4 at R464 residue. Integrin α-4 is predominantly expressed in infiltrating monocyte derived macrophages. Blocking monocyte infiltration into the liver with CCR2 inhibitor reduced fibrosis development in knockout mice and abolished differences between genotypes. Taken together, our data suggest that alcohol-mediated loss of Prmt6 contributes to alcohol-associated fibrosis development through reduced integrin methylation and increased profibrotic signaling in macrophages.
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DOI：
10.1016/j.bbadis.2012.10.005
发表时间：
2013-07
影响因子：
6.2
作者：
Henderson, Neil C.;Sheppard, Dean
通讯作者：
Sheppard, Dean
影响因子：
5.9
作者：
Ripamonti M;Liaudet N;Azizi L;Bouvard D;Hytönen VP;Wehrle-Haller B
通讯作者：
Wehrle-Haller B
DOI：
10.1111/acer.14700
发表时间：
2021-10
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.8
作者：
Chan, Lok Hei;Zhou, Lei;Ma, Stephanie
通讯作者：
Ma, Stephanie
影响因子：
4.8
作者：
Cheng, Donghang;Gao, Guozhen;Bedford, Mark T.
通讯作者：
Bedford, Mark T.