Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear.  ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice were fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibited protection against HFD–induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice displayed reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigated excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibited hepatic gluconeogenesis via the AMPK/CREB pathway and promoted glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provided novel evidence that ADAR2 KO protected against NAFLD progression through activation of AMPK signaling pathways. Overall design: ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice were fed with standard chow (CHOW) or high-fat diet (HFD) at the age of 5 week for 12 weeks. Mouse liver were isolated for RNA extract. Samples type: mouse liver samples; Replicates: duplicate; Groups:HFD_WT, HFD_KO