Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis.
Bing ZhouYunchen LuoNana JiCheng HuYan LuPublished in: Nature metabolism (2022)
Non-alcoholic fatty liver disease (NAFLD) is caused by imbalance in lipid metabolism. In this study, we show that the hepatokine orosomucoid (ORM) 2 is a key regulator of de novo lipogenesis in the liver. Hepatic and plasma ORM2 levels are markedly decreased in obese murine models and patients with NAFLD. 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 to activate AMP-activated protein kinase signaling, thereby inhibiting sterol regulatory element binding protein 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, non-alcoholic steatohepatitis and related lipid disorders.
Keyphrases
- body weight
- binding protein
- protein kinase
- fatty acid
- randomized controlled trial
- transcription factor
- high fat diet induced
- mouse model
- adipose tissue
- metabolic syndrome
- insulin resistance
- signaling pathway
- type diabetes
- quality improvement
- dna methylation
- emergency department
- gene expression
- stem cells
- cell therapy
- skeletal muscle
- risk assessment
- human health