Non-alcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD), which is tightly linked to overnutrition and obesity. Hepatic cell death, including apoptosis, is an important driver of NASH pathology. Saltiel and colleagues now show that NASH-associated hepatocyte apoptosis is inhibited by AMPK — a major sensor of cellular energy status.

Credit: S.Bradbrook /Springer Nature Limited

AMPK downregulation was previously associated with NAFLD. In line with this, mice on NASH-inducing diets had reduced AMPK activity. Furthermore, generation of liver-specific AMPK knock-out (LAKO) mice demonstrated that loss of AMPK exaggerates diet-induced NASH pathology, including increased liver damage, fibrosis and cell death — specifically apoptosis.

Apoptosis is driven by the caspase cascade, which involves a series of protein cleavage and activation steps. Cleavage of pro-caspase 6 to its mature form and subsequent caspase 6 activation were elevated in LAKO mice on NASH-inducing diets. Depletion or inhibition of caspase 6 counteracted NASH-associated liver pathology in these mice. Caspase 6 activity was also increased in other mice models of NASH and in liver samples from patients with NASH, indicating a key role of caspase 6 in hepatocyte apoptosis in NASH.

Mechanistically, pro-caspase 6 activation was shown to rely on caspase 3 and caspase 7, which are major executioners of apoptosis. Following activation, caspase 6 promoted the release of cytochrome c from mitochondria, thereby supporting activation of the executioner caspases and apoptosis in a feed-forward mechanism.

Pro-caspase 6 was directly phosphorylated by AMPK, and activation of AMPK reduced pro-caspase 6 cleavage in a cell culture model of hepatotoxicity. Together with the data from LAKO mice, this indicated that AMPK is an inhibitor of caspase 6-driven hepatic cell death in NASH.

AMPK is an inhibitor of caspase 6-driven hepatic cell death

Application of an agonist of AMPK to mice with diet-induced NASH was associated with pro-caspase 6 phosphorylation and with reduced caspase 6 activity. This approach also significantly reduced the number of apoptotic cells and alleviated liver damage. Thus, targeting the AMPK–caspase 6 axis could be explored as a new therapy for NASH.