Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression  

作　　者：Xiyue Shen Kai Luo Juntao Yuan Junling Gao Bingqing Cui Zhuoran Yu Zhongbing Lu 

机构地区：[1]College of Life Science,University of Chinese Academy of Sciences,Beijing 100049,China [2]Institute of Respiratory Medicine,Tongji University School of Medicine,Shanghai 200433,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第8期3352-3364,共13页药学学报（英文版）

基　　金：supported by grants from National Natural Science Foundation of China(82070250,32200631);Beijing Natural Science Foundation(5222029,China);China Postdoctoral Science Foundation(2022T150640);the Fundamental Research Funds for the Central Universities。

摘　　要：Dimethylarginine dimethylaminohydrolase 1(DDAH1)is an important regulator of plasma asymmetric dimethylarginine(ADMA)levels,which are associated with insulin resistance in patients with nonalcoholic fatty liver disease(NAFLD).To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD,we used hepatocyte-specific Ddah1-knockout mice(Ddah1HKO)to examine the progress of high-fat diet(HFD)-induced NAFLD.Compared to diet-matched flox/flox littermates(Ddah1f/f),Ddah1HKO mice exhibited higher serum ADMA levels.After HFD feeding for 16 weeks,Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice.On the contrary,overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice.RNA-seq analysis showed that DDAH1 affects NF-kB signaling,lipid metabolic processes,and immune system processes in fatty livers.Furthermore,DDAH1 reduces S100 calcium-binding protein A11(S100A11)possibly via NF-kB,JNK and oxidative stress-dependent manner in fatty livers.Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice.In summary,our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice.Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.

关 键 词：ADMA DDAH1 Hepatic steatosis INSULINRESISTANCE S100A11 OXIDATIVESTRESS Inflammation Highfat diet 

分 类 号：R57[医药卫生—消化系统]