Xu Min-Xuan, Tan Jun, Ge Chen-Xu, Dong Wei, Zhang Li-Ting, Zhu Lian-Cai, Zhao Jun-Jie, Wang Long-Yan, Liu Jin, Wei Hao, Sun Yan, Dai Xian-Ling, Kuang Qin, Li Yan-Liang, Li Han, Liu Jun-Yan, Zou Lei, Liang Ran-Ran, Zhang Chu-Feng, Xu Juan, Wang Bo-Chu
Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region , School of Biological and Chemical Engineering , Chongqing University of Education , Chongqing , PR China.
Key Laboratory of Biorheological Science and Technology (Chongqing University) , Ministry of Education , College of Bioengineering , Chongqing University , Chongqing , PR China.
Hepatology. 2023 Jan 1;77(1):124-143. doi: 10.1002/hep.32526. Epub 2022 Jul 7.
As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated.
We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, up-regulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus, or adeno-associated virus-mediated Trim31 gene therapy restrain NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7 and conjugates K48-linked ubiquitination chains to promote MAP3K7 degradation, thus blocking MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes.
TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders.
作为一种全球健康威胁，非酒精性脂肪性肝炎（NASH）已被确认为一种与肥胖密切相关的慢性进行性肝病。然而，目前尚无获批药物或有效的治疗策略，主要原因是其复杂的病理过程被低估。
我们鉴定出E3泛素连接酶家族成员之一的RING型E3泛素转移酶——含三联基序蛋白31（TRIM31），它是转化生长因子-β激活激酶1（丝裂原活化蛋白激酶激酶激酶7；MAP3K7）的有效内源性抑制剂。我们进一步证实TRIM31是一种与MAP3K7相互作用的蛋白，并通过增强肝细胞中K48连接的泛素化促进MAP3K7降解。肝细胞特异性Trim31缺失会破坏肝脏代谢稳态，同时伴有葡萄糖代谢综合征、脂质蓄积、炎症上调，并显著促进NASH进展。相反，转基因过表达、慢病毒或腺相关病毒介导的Trim31基因治疗可在三种饮食诱导的小鼠模型中抑制NASH。机制上，在应对代谢损伤时，TRIM31与MAP3K7相互作用，并结合K48连接的泛素化链以促进MAP3K7降解，从而阻断肝细胞中MAP3K7的丰度及其下游信号级联激活。
TRIM31可能是NASH治疗及相关代谢紊乱的一个有前景的治疗靶点。
