Exploring the role of ADAR2 in metabolic disorder

Abstract

Metabolic disorders are diseases that disrupt normal metabolism including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) NAFLD is a chronic disease caused by a build-up of fat in the liver Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA catalyzed by adenosine deaminase acting on RNA (ADAR) ADAR family contains ADAR1 ADAR2 and ADAR3 Previous study showed that high glucose induced upregulated ADAR2 expression in pancreatic INS-1 β cells ADAR2 may thus play an important role in metabolic regulation In this study we aimed to investigate the role of ADAR2 in the metabolic disorder progression We fed male and female mice with standard chow or high-fat-diet (HFD) in wild type (WT) and ADAR2-knockout (ADAR2-KO) mice for 12 weeks starting at the age of 5 weeks Daily food intake water intake and body weight were measured The analysis of metabolic parameters was determined Metabolic pathways (e g Insulin signaling pathway fatty acid synthesis gluconeogenesis and glycogen storage) were studied ADAR2-KO male mice fed with HFD had lower body weight compared with WT fed with HFD ADAR2-KO male mice fed with HFD showed improved glucose tolerance insulin resistance as well as decreased gluconeogenesis and increased glycogen storage ADAR2-KO male mice fed with HFD displayed a lipid profile with decreased plasma triglycerides (TG) free fatty acid and low-density lipoprotein (LDL) ADAR2-KO male mice fed with HFD displayed reduced liver lipid droplets in concert with decrease hepatic TG content Interestingly there was lower expression of de novo lipogenesis-related protein such as sterol regulatory element-binding protein 1 (SREBP-1) acetyl-coA carboxylase (ACC) fatty acid synthase (FAS) and stearoyl-CoA desaturase1 (SCD1) in the liver of ADAR2-KO male mice fed with HFD We also found that ADAR2-KO male mice fed with HFD had a reduced lipogenesis and gluconeogenesis via AMP-activated protein kinase (AMPK) signaling in the liver Moreover decreased insulin-like growth factor binding protein-7 (IGFBP7) expression was observed in the liver of ADAR2-KO male mice fed with HFD compared with that of control These results provide novel evidence that ADAR2-KO improved HFD-induced metabolic dysfunctions and prevented liver against TG accumulation

Date of Award	2020
Original language	English
Supervisor	Yun-Wen Chen (Supervisor)