Selective activation of AMPK in eddothelial cells intensifies high fat diet-induced non-alcoholic fatty liver disease

Abstract

BACKGROUND AND AIMS: AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that acts as a master regulator for glucose and lipid homeostasis. The hepatoprotective function of AMPK has been demonstrated by both pharmacological and genetic studies. For example, metaformin, the anti-diabetic drug, and adiponectin, the anti-inflammatory adipokine, elicit their lipid depletion effects in liver partly through activation of AMPK. A transgenic mouse model overexpressing a constitutively active form of AMPK (E-CA-AMPK) selectively in endothelial cells was established in our laboratory. The present study aimed to characterize the metabolic phenotypes of these mice under both standard chow and high fat diet conditions, with special focus on liver functions. METHODS: From the age of four weeks, mice were randomly assigned into groups fed with standard chow or high fat diet. Metabolic parameters, including body weight, fat mass and plasma glucose, were monitored at 2-week intervals. Systemic insulin sensitivity was evaluated by glucose and insulin tolerance tests. At 24 weeks of age, mice were sacrificed for hepatic functional examination, using biochemical, molecular and histological assays. RESULTS: No significant metabolic differences were observed between wild type C57 and E-CA-AMPK mice under standard chow. Compared with wild type mice, E-CA-AMPK mice showed increased body weight gains and impaired glucose tolerance under high fat diet condition. The percentage fat mass was significantly augmented in E-CA-AMPK mice. High fat diet induced more severe hepatosteatosis in E-CA-AMPK mice than that of wild type C57 mice. Hepatic injury markers, including serum levels of aspartate aminotransferase and alanine aminotransferase, and proinflammatory cytokine TNF-a expression in liver were augmented to a significantly higher level in E-CA-AMPK mice. The gene expression of low density lipoprotein receptor (LDL-R) and endothelial lipase was dramatically decreased in the liver tissues of E-CA-AMPK mice. CONCLUSIONS: Constitutive activation of AMPK in endothelial cells promotes the development of dietary obesity and enhances high fat diet-induced non-alcoholic fatty liver diseases.