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 Xiyue Shen;Kai Luo;Juntao Yuan;Junling Gao;Bingqing Cui;Zhuoran Yu;Zhongbing Lu

作者机构：College of Life ScienceUniversity of Chinese Academy of SciencesBeijing 100049China Institute of Respiratory MedicineTongji University School of MedicineShanghai 200433China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第8期

页      面：3352-3364页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

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 

主　　题：ADMA DDAH1 Hepatic steatosis Insulinresistance S100A11 Oxidativestress Inflammation Highfat diet 

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 *** to diet-matched flox/flox littermates(Ddah1f/f),Ddah1HKO mice exhibited higher serum ADMA *** HFD feeding for 16 weeks,Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f *** the contrary,overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob ***-seq analysis showed that DDAH1 affects NF-kB signaling,lipid metabolic processes,and immune system processes in fatty ***,DDAH1 reduces S100 calcium-binding protein A11(S100A11)possibly via NF-kB,JNK and oxidative stress-dependent manner in fatty *** of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO *** summary,our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese *** to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.