2019 Theses Doctoral

Hepatocyte Notch in non-alcoholic steatohepatitis (NASH)-associated liver fibrosis and cancer

Zhu, Changyu

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease associated with the worldwide spread of obesity. NASH predisposes development of fibrosis and hepatocellular carcinoma (HCC), but has no approved therapy due to incomplete understanding of the pathogenesis. Notch signaling normally specifies cell fate during development, but here we investigate how this pathway becomes dysregulated in NASH and contributes to fibrosis and cancer. In the first study, we show that hepatocyte Notch activity tracks with disease severity and treatment response in NASH patients, and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Different genetic models demonstrate causatively that hepatocyte Notch induces liver fibrosis via secretion of the fibrogenic factor Osteopontin that activates hepatic stellate cells (HSCs), while pharmacologic inhibition of hepatocyte Notch could ameliorate NASH-associated fibrosis. In the second study, we research how hepatocyte Notch activation leads to HCC in mice on NASH diet. Transcriptomic analysis reveals nerve growth factor (NGF) as a Notch target gene in hepatocytes, and the abundance of hepatocyte NGF precursor protein (proNGF) is uniquely associated with HCC. We provide evidence that proNGF may facilitate HCC growth and expansion in a non-cell autonomous manner by inducing HSC deactivation and fibrosis remodeling. In summary, hepatocyte Notch maladaptively contributes to fibrogenesis and possibly HCC expansion by directly signaling to HSCs at different stages of NASH progression, and could be an accessible target for treatment of NASH-associated liver pathologies.