AMPK activation in the treatment of liver disease

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic lipid accumulation, is most common liver disorder with an estimated prevalence of 20-30%. The spectrum of liver pathology in NAFLD ranges from steatosis to more serious disorders, such as non-alcoholic steatohepatitis, fibrosis and chirrosis with increased risk of liver failure and development of hepatocellular carcinoma. Furthermore, NAFLD is an important risk factor for chronic diseases, such as type 2 diabetes and cardiovascular disease.Despite the prevalence and seriousness of complications, the only currently accepted treatment for NAFLD are lifestyle changes leading to weight reduction. However, these benefits are often mitigated by high attrition rates and weight gain rebound highlighting the need for novel pharmaceutical strategies to improve NAFLD.The AMP-activated protein kinase (AMPK) is a cellular energy-sensing enzyme that is activated in response to energy stress. Once activated, AMPK promotes ATP-generating catabolic pathways and inhibits ATP-consuming anabolic pathways to restore energy balance. AMPK effects on lipid metabolism include the reduction of intracellular lipid levels through inhibition of de novo lipogenesis and promotion of fatty acid oxidation. AMPK activity is reduced in obesity and type 2 diabetes, the most common conditions associated with NAFLD. AMPK activation has therefore been proposed as an attractive strategy for the improvement of hepatic steatosis. We have utilized mouse models with knock-in mutations of the AMPK phosphorylation sites in acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), the rate-limiting enzymes in the de novo synthesis of fatty acids and cholesterol, respectively. We show in vivo evidence for AMPK's role as an essential regulator of liver lipid metabolism with significant effects on steatosis and hepatic insulin resistance. Inhibition of ACC activity by AMPK directly reduces hepatic lipid content by inhibiting hepatic fatty acid synthesis and promoting fatty acid oxidation. In addition, we find that on a high-carbohydrate diet AMPK suppression of cholesterol synthesis indirectly contributes to the reduction of hepatic triglyceride levels by preventing increases in lipogenic gene expression. Our results indicate that inhibition of lipid synthesis by AMPK activation may provide a treatment strategy for NAFLD.