The circFASN/miR-33a pathway participates in tacrolimusinduced dysregulation of hepatic triglyceride homeostasis  

作　　者：Chenzhi Zhang Kangchen Chen Rongli Wei Guanghan Fan Xuechun Cai Li Xu Beini Cen Jianguo Wang Haiyang Xie Shusen Zheng Xiao Xu 

机构地区：[1]Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310000,China [2]Key Lab of Combined Multi-Organ Transplantation,Ministry of Public Health,Hangzhou 310000,China [3]Department of Hepatobiliary and Pancreatic Surgery,Shulan(Hangzhou)Hospital,Hangzhou 310000,China

出　　处：《Signal Transduction and Targeted Therapy》2020年第1期2132-2141,共10页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China(General Program)[Grant number:81570589];the National Natural Science Funds for Distinguished Young Scholars of China[Grant number:81625003];the National Natural Science Foundation of China(Key Program)[Grant number:81930016];the Cheung Kong Scholars Program of China and National Science and Technology Major Project[Grant number:2017ZX100203205].

摘　　要：Dyslipidemia exhibits a high incidence after liver transplantation,in which tacrolimus,a widely used immunosuppressant,plays a fundamental role.MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism.However,their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear.In this study,we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins(SREBPs)and miR-33a.Our in silico and experimental analyses identified miR-33a as a direct target of circFASN.Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro.Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation.Clinically,the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a(46.3%vs.18.8%p=0.012,n=73).Our results showed that the circFASN/miR-33a regulatory system plays a distinct role in tacrolimus-induced disruption of lipid homeostasis.MiR-33a is likely a risk factor for tacrolimus-related dyslipidemia,providing a potential therapeutic target to combat tacrolimus-induced dyslipidemia after liver transplantation.

关 键 词：TACROLIMUS HOMEOSTASIS ELEVATED 

分 类 号：R96[医药卫生—药理学]