Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease

Abstract

Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1+/−) male mice were examined for liver injuries. Osr1+/− mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1+/− mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1+/− liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1+/− liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1+/− and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.