Caspase 1-mediated regulation of fibrogenesis in diet-induced steatohepatitis

Nonalcoholic Fatty Liver Disease (NAFLD) is currently the most common form of chronic liver disease affecting both adults and children, and is strongly associated with obesity and insulin resistance (1, 2). One in three adults and one in ten children or adolescents in the United States have hepatic steatosis, a stage within the spectrum of NAFLD, that is characterized by triglyceride accumulation in liver cells and follows a benign non-progressive clinical course (3, 4). Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with evidence of cellular damage, inflammation and different degrees of scarring or fibrosis (5). NASH is a serious condition as approximately 25% of these patients progress to cirrhosis and its feared complications of portal hypertension, liver failure and hepatocellular carcinoma (6-8). The pathogenesis of NAFLD/NASH in particular the mechanisms responsible for liver injury and disease progression remains incompletely understood but are of significant biomedical importance as identification of these processes may help to identify novel diagnostic and therapeutic targets for this highly prevalent and potentially serious disease. Since the original description that caspase activation and hepatocyte apoptosis are characteristic pathologic features in the liver of NASH patients (9), a growth of data have demonstrated a key role for caspase-dependent cell death in NASH pathogenesis (10-13). Caspases are a family of cysteine proteases with unique substrate specificities that play a central role in the apoptotic machinery (14, 15). They are synthesized as inert zymogens and upon receipt of apoptotic stimuli, cells activate initiator caspases such as caspase 1, 2, 8, 9, and 10 that, in turn, proteolytically cleave and activate effector caspases including caspase 3, 6, and 7. Caspases have been further categorized as either proinflammatory or proapoptotic, depending upon their participation in these cellular programs. The proinflammatory caspases include caspase 1, 11 and 12 in mouse and caspase 1, 4, and 5 in human (16). Targeting caspase activity and apoptosis has gained significant attention for developing of novel therapeutic diagnostic strategies for NASH patients. Recent data suggest that pan-caspase inhibition protects again diet-induced steatohepatitis in different dietary murine models (17-19). These pan-caspase inhibitors, not only inhibit caspase-mediated cellular apoptosis, but also block the caspase 1-dependent processing and activation of various proteins with functions in inflammation and tissue repair during tissue damage. However, the contribution of caspase 1-dependent processes to liver injury and fibrosis remains unclear. In the present study we examined the occurrence and significance of caspase 1 activation in NASH.