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| 1 | Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis显示文摘Complement is known to play a role in alcoholic fatty liver disease (AFLD), but the underlying mechanisms are poorly understood, thereby constraining the development of a rational approach for therapeutic intervention in the complement system. C3 deficiency has been shown to impart protective effects against ethanol-induced hepatic steatosis and inflammation. Here we demonstrate a protection effect in wild-type mice by treatment with CR2-Crry, a specific inhibitor of C3 activation. The expression of glycine transfer (t) RNA-derived fragments (Gly-tRFs) is upregulated in ethanol-fed mice and inhibition of Gly-tRFs in vivo decreases chronic ethanol feeding-induced hepatosteatosis without affecting inflammation. The expression of Gly-tRF was downregulated in C3-deficient or CR2-Crry-treated mice, but not in C5-deficient mice;Gly-tRF expression was restored by the C3 activation products C3a or Asp (C3a-des-Arg) via the regulation of CYP2E1. Transcriptome profiling of hepatic tissues showed that Gly-tRF inhibitors upregulate the expression of sirtuin1 (Sirt1) and subsequently affect downstream lipogenesis and β-oxidation pathways. Mechanistically, Gly-tRF interacts with AGO3 to downregulate Sirt1 expression via sequence complementarity in the 3′ UTR. Notably, the expression levels of C3d, CYP2E1 and Gly-tRF are upregulated, whereas Sirt1 is decreased in AFLD patients compared to healthy controls. Collectively, our findings suggest that C3 activation products contribute to hepatosteatosis by regulating the expression of Gly-tRF. Complement inhibition at the C3 activation step and treatment with Gly-tRF inhibitors may be potential and precise therapeutic approaches for AFLD. | Fudi Zhong Zhigao Hu Keqing Jiang Biao Lei Zhan Wu Guandou Yuan Hongliang Luo Chunqiang Dong Bo Tang Chaowen Zheng Shuai Yang Yonglian Zeng Zhenya Guo Shuiping Yu Huizhao Su Guo Zhang Xiaoqiang Qiu Stephen Tomlinson Songqing He | 2019 | Cell Research2019，29，7： | 14 |
| 2 | Production of monoclonal antibodies against AFLD(Nor-1),an early key protein involved in aflatoxin biosynthesis显示文摘Aflatoxins are distributed worldwide throughout environment. As many as 30genes are involved in aflatoxin biosynthesis. aflD (nor-1) was predicted to encode a 31 kDa ketoreductase (AFLD), which catalyzed the earliest and first stable aflatoxin precursor in aflatoxin biosynthetic pathway. AFLD was proved to be necessary for conversion of norsolorinic acid (NA) to averatin (AVN) in aflatoxin biosynthesis. For this reason, aflD was cloned and specific monoclonal antibodies for AFLD were developed to better define potential pathways of AFLD involved in Aflatoxin B_1 (AFB_1) biosynthesis. Monoclonal antibodies 2A8-1E10 and 2F11-3D8 were successfully screened out by immunized mouse. Immunoblot analysis revealed that 2A8-1E10 had high sensitivity and specificity to identify native AFLD protein in A. flavus with detection limit of 3 ng/mL. These results showed that it was suitable for quantitative detection of AFLD in A. flavus isolate. Further investigation revealed that aflatoxin accumulations of various A. flavus were not dependent on AFLD biosynthesis.Overall, this is the first report for AFLD monoclonal antibody development and application in A. flavus quantitative detection. | Ting Wang Peiwu Li Qi Zhang Wen Zhang Zhaowei Zhang Xueli Dong Tong Wang | 2018 | Oil Crop Science2018，3，1： | 0 |
| 3 | Investigating the Effect of Metabolic Phenotypes on Health Events in Alcoholic and Nonalcoholic Fatty Liver Disease显示文摘Background and Aims:Metabolic dysfunction and obe-sity commonly coexist with both alcoholic and nonalcoholic fatty liver disease(AFLD and NAFLD).The association of AFLD and NAFLD with incident diseases in individuals with different metabolic phenotypes are unclear.Methods:UK Biobank study participants were screened for the presence of fatty liver at baseline.Body mass index and metabolic dysfunction were used to define metabolic phenotypes.Cox regression model was performed to examine the associations of AFLD and NAFLD with incident significant liver diseases(SLDs),cardiovascular diseases(CVDs),chronic kidney dis-eases(CKDs),and cancers,respectively.Results:A total of 43,974 AFLD and 103,248 NAFLD cases were identified.Both AFLD and NAFLD were associated with an increased risk of diseases of interest.The effects were amplified by obesity and metabolic abnormalities and modified by metabolic phe-notypes.Compared to individuals free of fatty liver and with phenotype of metabolically healthy-normal weight,AFLD[hazard ratio(HR 3.27;95%CI:1.95-5.47)]and NAFLD(HR 2.25;95%CI:1.28-3.94)cases with phenotype of met-abolically obese-normal weight had the greatest risk of SLDs.For CVDs,CKDs,and cancer,the greatest risks were detected in AFLD and NAFLD cases with phenotype of metabolically obese-overweight/obesity.In this subpopulation,AFLD and NAFLD conferred a 2.75-fold(95%CI:2.32-3.25)and 4.02-fold 95%CI:(3.64-4.43)increased risk of CVDs,4.37-fold 95%CI:(3.38-5.64)and 6.55-fold 95%CI:(5.73-7.48)increased risk of CKDs,and 1.19-fold 95%CI:(1.08-1.27)and 1.21-fold 95%CI:(1.14-1.28)increased risk of cancers,respectively.Conclusions:Metabolic phenotypes modified the association of AFLD and NAFLD with intrahepatic and ex-trahepatic diseases. | Hong Fan Pengyan Zhang Zhenqiu Liu Renjia Zhao Chen Suo Xingdong Chen Tiejun Zhang | 2023 | Journal of Clinical and Translational Hepatology2023，11，3： | 0 |
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