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

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/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ 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/EBPδ and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.


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Sample size was chosen taking in consideration the means of the target values between the experimental group and the control group, the mean standard error and the statistical analysis used. For animal studies, sample size was defined on the basis of past experience with the models, to allow a power #80% at the 5% significance level. For ethical reasons, the minimum number of animals necessary to achieve the scientific objectives was used. The determination and justification of animal numbers for this work is performed according to the Laboratory Animal -Guide Line for Ethical Review of Animal of China (GB/T 35892-2018) and the Academic Committee of Experimental Animal Ethics, Use & Care Union in Chongqing University of Education.
No data were excluded in the current work when performing the final statistical analysis,which have been provided state in "Statistical analysis" section.
All in vitro experiments were performed in triplicate unless specified in the figure legends. The detailed replication of each experiments has been provided in Figure Legend.
For animal experiments, age-matched mice with different genotypes were randomly divided into different experimental groups. For cell culture experiments, cells with different genotypes or treatments were randomly divided into different experimental groups.
The investigators were unaware of the experimental groups in all the quantifications.
All antibodies used in our study have been validated and detailed information could be found on the websites from manufactures as nature portfolio | reporting summary
Human L02 cell line were verified by short tandem-repeat DNA profiling before the study.
Human L02 cell line were used immediately after being received he Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China) and certified as Mycoplasma free.
No misidentified cell lines were used in this study.
To minimize the effects of hormones oscillation on metabolism, only male animals (6-8 weeks old) were used for all experiments in this work. Before the experiment starts, animals participating in the corresponding experiment were forced to accommodate to their living environment for 7 days. The animals were kept at a steady temperature, moisture capacity (governed by Haier central air conditioning, Cat: RFC140MXSCVD/G, China), and aseptic conditions-controlled environment (25°C, 55 %-60 %) cage with a constant and standard 12/24 h-12/24 h light/dark circle, unlimited pathogen-free-drinking water (Cat: 1010004000, C'estbon, China) and fodder in their houses. For rabbit in vivo experiment, according to previous report with certain modification (26-28), 20 male New Zealand white rabbits (1.75-2.00 kg BW) were treated with corresponding HFHC diet (standard diet with an additional 2% maltodextrin, 2% cholesterol, and 10% saturated fats, Cat: 621079; Dyets, Bethlehem, Pa) for 8 weeks to establish rabbit NASH model. The rabbits were kept at a steady temperature, moisture capacity (governed by Haier central air conditioning, Cat: RFC140MXSCVD/G, China), and aseptic conditions-controlled environment (25°C, 55 %-60 %) cage with a constant and standard 12/24 h-12/24 h light/dark circle, unlimited pathogen-free-drinking water (Cat: 1010004000, C'estbon, China) and fodder in their houses.