Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis

Alterations in hepatic lipid metabolism may contribute to the onset of non-alcoholic fatty liver disease as well as other metabolic disorders. In this work, Zhou et al. identify orosomucoid 2 (ORM2) as a regulator of lipid homeostasis in the liver. 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.

Automated summary

Alterations in hepatic lipid metabolism may contribute to the onset of non-alcoholic fatty liver disease. Zhou et al. identify orosomucoid 2 (ORM2) as a key regulator of lipid homeostasis in the liver. ORM2 activates the AMP-activated protein kinase signaling to inhibit lipogenesis. Additionally, injections of ORM2 protein improved liver steatosis and atherosclerosis.