The Metabolic Sensor Adenosine Monophosphate-Activated Protein Kinase Regulates Apoptosis in Nonalcoholic Steatohepatitis.

Abstract

Nonalcoholic steatohepatitis (NASH), occurring in a subset of patients with nonalcoholic fatty liver disease (NAFLD), is characterized by cellular inflammation and hepatic fibrosis. NASH may lead to the development of end-stage liver disease and its sequelae. Hepatocyte cell death contributes to inflammation and fibrosis in NASH. Although multiple modes of cell death occur in experimental models of NASH (i.e., apoptosis, necroptosis, and pyroptosis), apoptosis is the best characterized. Apoptosis is mediated by activation of a family of cysteine proteases termed caspases, which ultimately cleave a plethora of cellular substrates resulting in cellular demise. Caspases are classified as "initiators" (i.e., caspase-8, caspase-9) and "executioners" (i.e., caspase-3, caspase-7, caspase-6), the former being activated in molecular platforms assembled after engagement of death receptors or mitochondrial permeabilization, and the latter being cleaved and activated by initiator caspases, with the exception of caspase-6, which is often activated by caspase-3 rather than by initiator caspases. Although caspase-3 has been implicated in hepatocyte apoptosis and liver fibrosis in a mouse model of NASH (1), the involvement of caspase-6 was never reported until now.