Xu M, Tan J, Liu X, Han L, Ge C, Zhang Y, Luo F, Wang Z, Xue X, Xiong L, Wang X, Zhang Q, Wang X, Tian Q, Zhang S, Meng Q, Dai X, Kuang Q, Li Q, Lou D, Hu L, Liu X, Kuang G, Luo J, Chang C, Wang B, Chai J, Shi S, Han L

Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBP?), and we ...

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also confirm that TRIM26 is an C/EBP?-interacting partner protein that catalyses the ubiquitination degradation of C/EBP? in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression. Inversely, transgenic Trim26 overexpression attenuates the NASH-associated phenotype in a rodent or rabbit model. We provide mechanistic evidence that, in response to metabolic insults, TRIM26 directly interacts with C/EBP? and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.

Date: Oct. 11, 2023

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