Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet

AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma). [Display omitted] •A mutation in AMPKγ1 subunit leads to constitutive activation of the kinase•AMPK activation in liver protects against steatosis on a fructose diet•AMPK inhibits de novo lipogenesis with no effect on hepatic fatty acid oxidation•AMPK provides an attractive pharmacological target for protection against NAFLD Using a gain-of-function mouse model, Woods et al. show that hepatic activation of AMPK protects against triglyceride accumulation in the liver. AMPK inhibits de novo lipogenesis but has no effect on hepatic fatty acid oxidation. These findings highlight AMPK as an attractive therapeutic target for protection against fatty liver disease.