Shanghai Jiaotong University He Ming team reveals new mechanisms and new therapeutic targets for alcoholic liver disease​

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At present, the main prevention and treatment method for alcoholic liver disease is to abstain from alcohol, but even with complete abstinence, only 27% of patients' liver function can fully return to normal, and the remaining patients will eventually develop chronic hepatitis and cirrhosis
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Due to the complex pathogenesis of ALD, there is still no targeted drug treatment
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Recently, the team of Professor Ming He from the Department of Pathophysiology and the Key Laboratory of Cell Differentiation and Apoptosis of the Ministry of Education, Shanghai Jiaotong University School of Medicine published an online title: SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver in Cell Discovery.
Injury research papers
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The study found that liver cell SIRT2 can deacetylate C/EBPβ and inhibit its ubiquitination degradation through clinical data analysis, construction of liver gene-specific knockout mouse models, mouse gene therapy, and cell molecular biology research.
, And then up-regulate the downstream target gene LCN2, reducing lipid peroxidation and liver cell apoptosis caused by alcohol
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This research provides new therapeutic targets and strategies for the prevention and treatment of alcoholic liver disease (ALD)
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Sirtuin 2 (SIRT2) is a member of the silent information regulator (sirtuin) protein family.
It is a type of NAD+ dependent deacetylase that is highly expressed in the liver.
It can participate in aging and stress responses by deacetylating different substrates.
, Glycolipid metabolism, inflammatory response and other biological functions
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Professor He Ming’s research group has long focused on the study of protein acetylation modification and aging and liver metabolism-related diseases.
In March 2020, as the first author in Cell Metabolism, he reported that SIRT2 can inhibit the assembly of NLRP3 inflammasomes through deacetylation.
And activation, thereby reducing chronic inflammation and insulin resistance caused by aging or high-fat diet, suggesting that SIRT2 plays an important regulatory switch role in aging and metabolic diseases
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However, the function of SIRT2 in ALD is unclear
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The study started from clinical analysis and found that the expression of SIRT2 protein in liver samples of ALD patients was significantly negatively correlated with the severity of ALD
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Further use of liver SIRT2 specific knockout mice found that the specific lack of liver SIRT2 aggravated liver lipid deposition, lipid peroxidation and liver cell apoptosis caused by alcohol
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Using AAV8 to specifically overexpress SIRT2 in liver cells can completely inhibit alcohol-induced liver damage
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In terms of mechanism, RNAseq was first used to find that SIRT2 knockout can significantly inhibit the increase in acute phase response protein caused by alcohol.
In vivo and in vitro experiments have confirmed that hepatocyte acute phase response protein LCN2 (lipocaline-2) can significantly inhibit ALD and mediate Lead the protective effect of SIRT2 on ALD
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Through bioinformatics analysis and ChIP experiments, it is found that SIRT2 mainly up-regulates the transcriptional expression of LCN2 through C/EBPβ (CCAAT/enhancer-binding protein beta)
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However, SIRT2 in hepatocytes binds to C/EBPβ protein and deacetylates K102 and K211 to inhibit C/EBPβ ubiquitination degradation, increase its protein stability, and promote the transcription of its downstream target gene LCN2
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And more importantly, at the animal level, compared to wild-type C/EBPβ, the deacetylated C/EBPβ mutant can reverse the alcoholic liver damage aggravated by SIRT2 knockout
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Consistent with the results of the mechanism study, the expression of the SIRT2-C/EBPβ-LCN2 axis in the liver samples of clinical ALD patients was positively correlated, and was significantly negatively correlated with the degree of liver damage
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In conclusion, this study has discovered a new mechanism of liver self-protection during the occurrence of ALD, and the SIRT2-C/EBPβ-LCN2 axis may become a new target for the treatment of ALD
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 Professor Ming He and Professor Qian Zhao of Shanghai Jiaotong University School of Basic Medicine are the co-corresponding authors.
Master students Zhang Yingting and Ruan Xin in the research group, and Professor Long Xidai from Youjiang Medical College for Nationalities are the co-first authors of this paper
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The research work was helped and supported by Academician Chen Guoqiang, Professor Liu Junling, Professor Zhong Qing, Researcher Shen Shaoming, and Associate Professor Xia Li of Shanghai Jiaotong University School of Medicine
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The research has been funded by the National Natural Science Foundation of China, the major research plan cultivation project, the Shanghai Natural Science Fund, and the Pujiang Talent Program
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Link to the paper: https:// open for reprinting, welcome to forward to Moments and WeChat groups