Investigating the effect of chronic activation of AMP-activated protein kinase in the liver

Abstract

Obesity and its associated complications, are an increasing global problem. Non-alcoholic fatty liver disease (NAFLD), the hepatic component of the Metabolic Syndrome currently affects an estimated 25% of the world’s population, with 2% of those affected dying from a NAFLD liver related cause, such as hepatocellular cancer (HCC). AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis that regulates anabolic and catabolic pathways in response to ATP depletion has received substantial attention as a therapeutic target in treatment of the Metabolic Syndrome. More recently, a growing number of studies have focussed on the role of AMPK in cancer. This study has characterised a novel, activating mutation in the γ1 subunit of AMPK (D316A). Mice which express this mutation specifically in the liver (D316-Tg) have been used to investigate the effects of chronic hepatic AMPK activation under basal conditions and in response to the metabolic stresses of hypercaloric, high fat and lipogenic, high fructose diets. D316A-Tg mice have also been crossed with mice with liver specific Phospatase and tensin homologue (Pten) loss to evaluate the role of AMPK in NAFLD related HCC. Fatty acid synthesis was reduced in hepatocytes isolated from D316A-Tg mice and these mice were protected from hepatic steatosis under lipogenic conditions. Fatty acid oxidation in hepatocytes was unaffected by increased AMPK activity and correspondingly D316A-Tg mice were not protected from hepatic lipid accumulation, following high fat feeding. Increased hepatic AMPK activity also attenuated steatohepatitis and had a marked inhibitory effect on tumourgenesis in mice with liver specific Pten loss. Further work is required to elucidate the precise role of AMPK in tumour development. However, the findings of this study suggest that activation of AMPK in the liver may inhibit NAFLD progression and tumourgenesis and support the development of pharmacological, specific AMPK activators for use in these settings.