Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Gastroenterology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430000, China.
Cell Metab. 2021 Jul 6;33(7):1372-1388.e7. doi: 10.1016/j.cmet.2021.05.019. Epub 2021 Jun 18.
Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and liver disorders have become the leading causes for the need of liver transplantation in developed countries. Lipotoxicity plays a central role in NASH progression by causing endoplasmic reticulum stress and disrupting protein homeostasis. To identify key molecules that mitigate the detrimental consequences of lipotoxicity, we performed integrative multiomics analysis and identified the E3 ligase tripartite motif 16 (TRIM16) as a candidate molecule. In particular, we found that lipid accumulation and inflammation in a mouse NASH model is mitigated by TRIM16 overexpression but aggravated by its depletion. Multiomics analysis showed that TRIM16 suppressed NASH progression by attenuating the activation of the mitogen-activated protein kinase (MAPK) signaling pathway; specifically, by preferentially interacting with phospho-TAK1 to promote its degradation. Together, these results identify TRIM16 as a promising therapeutic target for the treatment of NASH.
非酒精性脂肪性肝炎（NASH）相关的肝细胞癌和肝脏疾病已成为发达国家肝移植需求的主要原因。脂肪毒性通过引起内质网应激和破坏蛋白质平衡，在 NASH 进展中起核心作用。为了确定减轻脂肪毒性有害后果的关键分子，我们进行了综合多组学分析，发现 E3 连接酶三联基序 16（TRIM16）是候选分子。特别是，我们发现，在小鼠 NASH 模型中，TRIM16 的过表达减轻了脂质积累和炎症，而其耗竭则加剧了这种情况。多组学分析表明，TRIM16 通过抑制丝裂原活化蛋白激酶（MAPK）信号通路的激活来抑制 NASH 的进展；具体而言，通过优先与磷酸化的 TAK1 相互作用来促进其降解。总之，这些结果表明 TRIM16 是治疗 NASH 的有前途的治疗靶点。
