UC San Diego

Hepatocellular carcinoma (HCC) is the second most deadly cancer worldwide, which can result from the progression of fatty liver disease (NAFLD) and steatohepatitis (NASH) to tumorigenesis. NAFLD is an increasing problem in the Western world with the rapid increase in obesity. It is the most commonly diagnosed condition in patients with liver disorders, and is present in 20-30% of adults in the United States. NASH is a more severe form of NAFLD characterized by inflammation and fibrosis, which can advance to cirrhosis and HCC. Our most recent study to elucidate the molecular mechanisms of HCC showed that two molecules, Shp2 and Pten, have a synergistic effect to prevent hepatocarcinogenesis. The deletion of Shp2 and Pten led to severely fatty livers and early-onset NASH and tumors. As mitochondria are the major site for fatty acid metabolism and source of ROS, we looked further to address how mitochondrial function is disrupted in this NASH model and whether mitochondrial dysfunction is likely contributing to the progression of NASH to HCC. We quantified the mitochondria and examined mitochondrial functions, including structure, integrity, motility, and gene expression. We show that mitochondrial structure and integrity were compromised in Pten knockout and Shp2/Pten double-knockout mice. Mitochondrial numbers were dramatically decreased in double-knockout mice. We also found that mitochondrial metabolic pathways are dysregulated in Pten knockout mice. These results demonstrate that dysfunctional mitochondria may contribute to the progression of NASH to HCC, and may be a good therapeutic target.