Metabolic Disease & Obesity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Victoria 3800, Australia
Obesity and its principal complication type 2 diabetes promote the development of non-alcoholic fatty liver disease (NAFLD); 80-90% of obese individuals have NAFLD. NAFLD on its own is considered to cause little harm or irreversible damage. However, in a subset of people, NAFLD can progress to the more severe form of the disease, non-alcoholic steatohepatitis (NASH) characterised by inflammation and fibrosis. Over prolonged periods of non-resolving inflammation, and persistent tissue remodelling, NASH/fibrosis can progress to cirrhosis. Fibrotic/cirrhotic livers may contain pre-malignant dysplastic foci with progenitors that can undergo malignant progression and develop into HCC. The molecular basis for the NAFLD to NASH progression and the development of HCC in obesity remain unclear. Moreover, the identification of individuals that have progressed to NASH and are therefore prone to develop HCC remains a major challenge. Inflammation and oxidative stress occur in the liver in obesity/type 2 diabetes and reactive oxygen species (ROS) such as H2O2 can oxidise and inactivate protein tyrosine phosphatases (PTPs) for the promotion of tyrosine phosphorylation-dependent signaling. We have reported previously that obesity-associated oxidative stress drives the oxidation and inactivation of PTPs such as TCPTP and PTP1B in the liver to promote STAT-1/3 signaling. Here we report that ROS in obesity and NAFLD inactivate PTPs to promote STAT-1/3 signalling and the progression from NAFLD to NASH and HCC. Our findings shed light on fundamental processes pertinent to the development of NASH and HCC and identify biomarkers that may ultimately afford novel opportunities for early diagnosis and therapeutic intervention.
References: 1. Gurzov, E.N., et al. (2014) Cell Metab 20, 85–102.