4.8 Article

Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation

Journal

NATURE COMMUNICATIONS
Volume 14, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-023-42040-9

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The E3 ligase TRIM26 is identified as a key suppressor in the development of NASH by inhibiting CCAAT/enhancer binding protein delta (C/EBP δ). This finding has important implications for the treatment and understanding of NASH.
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 delta), and we also confirm that TRIM26 is an C/EBP delta-interacting partner protein that catalyses the ubiquitination degradation of C/EBP delta 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 delta and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development. Nonalcoholic steatohepatitis (NASH) is a heterogeneous disease with complicated pathogenesis. Here the authors identify that the E3 ligase TRIM26 confers protection against NASH development via suppression of CCAAT/enhancer binding protein delta (C/EBP delta).

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