miR-1224-5p Enhances Hepatic Lipogenesis by Targeting Adenosine Monophosphate-Activated Protein Kinase α1 in Male Mice

Abstract

MicroRNAs are potential therapeutic targets for metabolic diseases. Here, miR-1224-5p was highly expressed in the livers of mice fed a high-fat diet (HFD) and in obese (ob/ob) mice. To examine the potential role of miR-1224-5p, we constructed liver-specific adenoviral vectors expressing either an miR-1224-5p inhibitor sequence or miR-1224-5p mimic sequences. After tail-vein vector injection, HFD-fed mice were examined for expression of lipogenic genes. We found that miR-1224-5p inhibitors significantly attenuated hepatic lipogenesis and steatosis in HFD-fed mice, whereas miR-1224-5p mimicked promoted lipid accumulation in the liver of chow-fed C57BL/6 mice. Additional in vitro studies demonstrated that downregulation of miR-1224-5p in HepG2 and primary hepatocytes led to a reduction of cellular triglycerides after treatment with an oleic acid and palmitic acid mixture. Importantly, this study also identified adenosine monophosphate-activated protein kinase (AMPK)-α1 as a direct target of miR-1224-5p. miR-1224-5p binding to the 3' untranslated region of AMPKα1 suppressed expression of the AMPKα1 protein and its downstream molecules. Metformin, an activator of AMPK, also inhibited hepatic expression of miR-1224-5p. Together, these findings indicate that miR-1224-5p promotes hepatic lipogenesis by suppressing AMPKα1 expression and suggest that miR-1224-5p inhibitors warrant further investigation as potential therapeutic tools in the treatment of nonalcoholic fatty liver disease.