Signal transducer and activator of transcriptions (STATs)—at the crossroads of obesity-linked non-alcoholic steatohepatitis and hepatocellular carcinoma

The obesity pandemic is widely regarded as major health challenge for modern society. This multi-organ disorder is linked to the development of a number of prevalent diseases, such as type 2 diabetes, cardiovascular and liver diseases, including primary liver cancer (1). The hepatic manifestations of obesity are collectively called non-alcoholic fatty liver disease (NAFLD) (2). The increased prevalence of NAFLD parallels the global obesity pandemic and is predicted to be the largest cause of liver transplantations (1). The term NAFLD encompasses different disease states, ranging from simple steatosis (NAFL) to more severe forms of liver disease such as non-alcoholic steatohepatitis (NASH), with various degree of fibrosis (3). NASH may progress to cirrhosis and hepatocellular carcinoma (HCC) (4). Although NASH arising from fatty liver disease seems to be an underlying lesion for some HCC cases, the extent to which the presence or the severity of NASH explains obesity-related HCC remains unclear (5). Moreover, HCC is increasingly diagnosed among obese individuals independent of NASH and cirrhosis (6), suggesting that cirrhosis is not necessary for the development of HCC in obesity. However, the precise mechanisms that give rise to HCC in some NASH patients and not in others remain largely unknown. A number of molecular mechanisms have been linked to obesity and its associated abnormalities that may facilitate the development of NASH and HCC, such as adipose tissue and hepatic inflammation, lipotoxicity and oxidative stress, and insulin resistance and ensuing hyperinsulinemia (7). These, and other pathological events in obesity, have complex interactions, so their relative contribution to the development of HCC in various stages of NAFLD progression remains to be determined. For example, the molecular mechanisms driving the recruitment and activation of immune cells contributing to NASH pathologies have remained unclear. Similarly, we have a poor understanding of the mechanisms involved in lipotoxicity and oxidative stress-induced NASH and HCC