Treatment of non-alcoholic steatohepatitis with recombinant Orosomucoid 2, an acute phase protein that attenuates the Erk1/2-PPARγ-Cd36 signaling pathway

Summary Therapeutic administration of recombinant proteins has been used for the treatment of various diseases in multiple studies. Herein, we investigated the function of the acute phase protein Orosomucoid 2 (Orm2), which is mainly secreted by hepatocytes, and evaluated its potential as a therapeutic strategy for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We here revealed that a high expression of Orm2 protected mice from high-fat diet (HFD)-induced obesity. The pharmacological administration of recombinant ORM2 protein attenuated hepatic steatosis, inflammation, hepatocyte injury, and fibrosis in mouse livers, which suffered NAFLD and NASH under dietary challenge conditions. Orm2 knockout mice spontaneously underwent obese after 16 weeks under normal diet. Orm2 deficiency exacerbated HFD-induced steatosis, steatohepatitis, and fibrosis in mice. Mechanistically, the deletion of Orm2 led to the activation of the Erk1/2-PPARγ-Cd36 signaling pathway, which in turn increased fatty acid uptake and absorption in hepatocytes and mice. Collectively, our results provide Orm2 is an essential factor for preventing NASH and associated NAFLD under obesity.