AMPK Activator AICAR Alleviated Lipopolysaccharide/D-Galactosamine-Inducd Acute Liver Injury

The AMP-activated protein kinase (AMPK) is a pivotal celluar energy sensor. AMPK is activataed under falling energy status and plays cruical roles in maintening energy homeostasis. A serie studies recently found that AMPK also has important regulatory effects on energy-intensive physiological or pathological responses such as inflammation. Our research group previously found that inhibition of the energy metabolism pathway in mitochondria effectively attenuated lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced acute liver injury. To further investigate the roles of low energy associated AMPK in LPS/D-Gal-induced liver injury, the potential effects of a widely used AMPK activator 5-amino-4-imidazolecarboxamide riboside (AICAR) were investigated in a mouse model with LPS/D-Gal-induced acute liver injury. Our experimental data indicated that (1) treatment with AICAR suppressed the elevation of plasma aminotransferases in a dose-dependent manner and these effects were accompanied with alleviated histopathological abnormalities in mice exposed to LPS/D-Gal. (2) Treatment with AICAR also inhibited the upregulation of tumor necrosis factor a (TNF-a), nitric oxide (NO) and myeloperoxidase (MPO), and these effects were accompanied with suppressed nuclear translocation of nuclear factor kappa B (NF-κB). (3) LPS/D-Gal exposure induced the upregulation of tissue factor, hypoxia-inducible factor-la (HIF-la), erythropoietin (EPO) and lactic acid (LA), but all of these elevations were suppressed by AICAR. (4) In addition, the LPS/D-Gal-induced the expression of Bax, increase of Bax/Bcl-2 and the subsequent induction of TUNEL-positive cells, cleavage of caspase-3, elevation of hepatic caspase-3,-8,-9 activities were all suppressed by AICAR. These evidence suggested that AMPK activator AICAR could attenuate LPS/D-Gal-induced acute liver injury, and the protective benefits of AICAR might be associated with its anti-inflammatory, anti-coagulatory and anti-apoptotic activities. These data suggested that AMPK might play protective roles in LPS/D-Gal-induced acute liver injury and AMPK might become a novel target for pharmacological intervention of inflammation-associated liver disorders.