Redox balance in the pathogenesis of nonalcoholic Fatty liver disease: mechanisms and therapeutic opportunities

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, non-progressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species (ROS) generation; additionally, the potential pathogenetic role of extracellular sources of ROS in NAFLD, including increased myeloperoxidase (MPO) activity and oxidized low density lipoprotein accumulation, will be reviewed. We will discuss how these mechanisms converge to determine the whole patho-physiological spectrum of NAFLD, including hepatocyte triglyceride accumulation, hepatocyte apoptosis, hepatic inflammation, hepatic stellate cell activation and fibrogenesis. Finally, available animal and human data on treatment opportunities with older and newer antioxidant will be presented.