Nonalcoholic fatty liver disease (NAFLD) has a wide spectrum of liver damage with a worldwide prevalence of almost 20%. AMP-activated protein kinase alpha 1 (AMPK alpha 1) is an energy sensor that plays a key role in regulating lipid metabolism of the liver. This study explores the role of AMPK alpha 1 overexpression in a steatotic hepatocyte model. The results displayed that the AMPK alpha 1 overexpression suppressed lipid accumulation in the cytoplasm, decreased triglyceride levels, maintained the survival of steatotic hepatocyte model with decreased cell apoptosis and increased survival rate. Besides, AMPK alpha 1 over expression promoted the expression of lipid catabolism-related genes, reduced the level of anabolism related genes, alleviated the inflammatory response by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Moreover, AMPK alpha 1 overexpression could inhibit the activation of p38 mitogen-activated protein kinase (p38MAPK). Finally, Anisomycin, a frequently-used activator of p38MAPK, reversed the inhibitory effect of pc-AMPK alpha 1 on the expression of p-p38MAPK, suggesting that AMPK alpha 1 overexpression alleviates inflammatory response through the inactivation of p38MAPK. These results indicated that AMPK alpha 1 may serve as a novel target:for treatment of NAFLD. (C) 2016 Elsevier Inc. All rights reserved.