Tripartite motif 38 alleviates the pathological process of NAFLD-NASH by promoting TAB2 degradation.
Tripartite motif 38 alleviates the pathological process of NAFLD-NASH by promoting TAB2 degradation.
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DOI：
10.1016/j.jlr.2023.100382
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发表时间：
2023-07
影响因子：
6.5
通讯作者：
Zhang, Peng
中科院分区：
文献类型：
--
作者：
Yao, Xinxin;Dong, Ruixiang;Hu, Sha;Liu, Zhen;Cui, Jie;Hu, Fengjiao;Cheng, Xu;Wang, Xiaoming;Ma, Tengfei;Tian, Song;Zhang, Xiao-Jing;Hu, Yufeng;Bai, Lan;Li, Hongliang;Zhang, Peng
非酒精性脂肪性肝病（NAFLD）已成为世界范围内最常见的慢性肝病，临床上没有任何FDA批准的药物干预。Trim 38作为TRIM家族的重要成员，参与天然免疫和炎症反应的调节。然而，TRIM 38在NAFLD中的功能作用在很大程度上仍然未知。在这里，TRIM 38的表达首先在NAFLD小鼠模型和诊断为NAFLD的患者的肝脏样品中检测到。我们发现TRIM 38在NAFLD肝组织中的表达与正常肝组织相比下调。体内遗传Trim 38-KO显示，TRIM 38缺失使高脂饮食和高脂和高胆固醇饮食诱导的肝脂肪变性以及高脂和高胆固醇饮食诱导的肝脏炎症和纤维化恶化。特别是，我们发现，肝细胞脂质积累和炎症诱导的棕榈酸和油酸的影响加剧了TRIM 38耗尽，但减轻了TRIM 38过表达在体外。在机制上，RNA-Seq分析表明TRIM 38通过减弱MAPK信号通路的活化来改善非酒精性脂肪性肝炎的进展。我们进一步发现TRIM 38与转化生长因子-β-活化激酶1结合蛋白2相互作用，促进其蛋白降解，从而抑制转化生长因子-β-活化激酶1-MAPK信号级联。总之，我们的研究表明，TRIM 38可以通过促进转化生长因子-β-活化激酶1结合蛋白2的降解来抑制NAFLD中的肝脂肪变性、炎症和纤维化。TRIM 38可能是NAFLD治疗的潜在靶点。
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide, without any Food and Drug Administration-approved pharmacological intervention in clinic. Trim38, as an important member of the TRIM (tripartite motif-containing) family, was largely reported to be involved in the regulation of innate immune and inflammatory responses. However, the functional roles of TRIM38 in NAFLD remain largely unknown. Here, the expression of TRIM38 was first detected in liver samples of both NAFLD mice model and patients diagnosed with NAFLD. We found that TRIM38 expression was downregulated in NAFLD liver tissues compared with normal liver tissues. Genetic Trim38-KO in vivo showed that TRIM38 depletion deteriorated the high-fat diet and high fat and high cholesterol diet-induced hepatic steatosis and high fat and high cholesterol diet-induced liver inflammation and fibrosis. In particular, we found that the effects of hepatocellular lipid accumulation and inflammation induced by palmitic acid and oleic acid were aggravated by TRIM38 depletion but mitigated by TRIM38 overexpression in vitro. Mechanically, RNA-Seq analysis demonstrated that TRIM38 ameliorated nonalcoholic steatohepatitis progression by attenuating the activation of MAPK signaling pathway. We further found that TRIM38 interacted with transforming growth factor-β-activated kinase 1 binding protein 2 and promoted its protein degradation, thus inhibiting the transforming growth factor-β-activated kinase 1-MAPK signal cascades. In summary, our study revealed that TRIM38 could suppress hepatic steatosis, inflammatory, and fibrosis in NAFLD via promoting transforming growth factor-β-activated kinase 1 binding protein 2 degradation. TRIM38 could be a potential target for NAFLD treatment.
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影响因子：
5.6
作者：
Hirata Y;Takahashi M;Morishita T;Noguchi T;Matsuzawa A
通讯作者：
Matsuzawa A
影响因子：
29.4
作者：
Cotter, Thomas G.;Rinella, Mary
通讯作者：
Rinella, Mary
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
DOI：
10.1038/nri2413
发表时间：
2008-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Ozato K;Shin DM;Chang TH;Morse HC 3rd
通讯作者：
Morse HC 3rd
影响因子：
6.3
作者：
Sumida Y;Yoneda M
通讯作者：
Yoneda M