SRA

Non-alcoholic fatty liver disease (NAFLD) is caused by imbalance in lipid metabolism. In this study, we show that the hepatokine Orosomucoid 2 (ORM2) is a key regulator of de novo lipogenesis in the liver. Hepatic and plasma ORM2 levels are markedly decreased in obese murine models and NAFLD patients. Through multiple loss- and gain-of function studies, we demonstrate that ORM2 is essential to maintain hepatic and systemic lipid homeostasis. At the mechanistic level, ORM2 binds to inositol 1, 4, 5-trisphosphate receptor type 2 (ITPR2) to activate AMP-activated protein kinase (AMPK) signaling, thereby inhibiting sterol regulatory element binding protein 1c (SREBP-1c)-mediated lipogenic gene program. Notably, intraperitoneal injections of recombinant ORM2 protein or stabilized ORM2-FC fusion protein markedly improved liver steatosis, steatohepatitis and atherosclerosis in preclinical mouse models, without adverse effects on body weight or food intake. Thus, these findings suggest that ORM2 may serve as a potential target for therapeutic intervention in NAFLD, NASH and related lipid disorders. Overall design: Male ob/ob mice were purchased from GemPharmatech Company (Nanjing, China). Mice were randomly divided into two groups and administered with adenovirus containing GFP or ORM2 (1×10E9 plaque-forming units/mouse) through tail vein injection, respectively. 12 days later, mice were sacrificed and liver tissues were harvested for RNA-Seq analysis and other experiments. The objective of RNA-Seq is to identify potential target genes of ORM2 in improving liver steatosis. In our datasets, Ad-GFP means ob/ob mice transduced with adenovirus containing GFP. Ad-ORM2 means ob/ob mice transduced with adenovirus containing ORM2. n=4 in each group.