Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis  

作　　者：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 

机构地区：[1]Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi, China [2]Laboratory of Liver Injury and Repair, Nanning, Guangxi, China [3]Department of Gastroenterology, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China [4]Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

出　　处：《Cell Research》2019年第7期548-561,共14页细胞研究（英文版）

基　　金：supported in part by the State Key Program of the National Natural Science Foundation of China(81430014);the National Natural Science Foundation of China(81660103,81771674 and 81860654);111 Project(D17011);the National Institutes of Health(R01DK102912);Guangxi BaGui Scholars,Project of Guangxi Health and Family Planning Commission(S201602);Basic Ability Promotion Project of Guangxi(2017KY0481);Natural Science Foundation of Gyangxi(2015GXNSFFA139004,2016JJB140027);the Project of Traditional Chinese Medicine of Guangxi Health and Family Planning Commission(GZLC16-47);the Project of Guangxi University Collaborative Innovation Center;Guangxi Digestive Disease Clinical Medical Research Center Construction Project(AD17129027).

摘　　要：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.

关 键 词：COMPLEMENT disease AFLD 

分 类 号：Q[生物学]