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Cell death & disease

Endogenous AMPK acts as a detrimental factor in fulminant hepatitis via potentiating JNK-dependent hepatocyte apoptosis.


PMID 28252653

Abstract

The energy sensor AMP-activated protein kinase (AMPK) is crucial for energy homeostasis. Recent studies have revealed that AMPK is involved in various energy-intensive pathological processes such as inflammation and apoptosis. The physiological functions of hepatic AMPK have been well studied, but the pathological significance of AMPK in liver disorders remains largely unknown. In the present study, the phosphorylation status and the roles of AMPK were investigated in mice with lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced fulminant hepatitis. The experimental data indicated that the phosphorylation of hepatic AMPK increased in mice with LPS/D-Gal-induced fulminant hepatitis. Pretreatment with the AMPK inhibitor compound C enhanced the early production of pro-inflammatory cytokines but suppressed the late activation of the caspase cascade, reduced the number of TUNEL-positive cells, decreased the elevation of aminotransferases, alleviated the histological abnormalities and improved the survival rate of LPS/D-Gal-insulted mice. Pretreatment with compound C suppressed LPS/D-Gal-induced phosphorylation of JNK. Inhibition of JNK alleviated LPS/D-Gal-induced liver injury, but the level of p53 remained unchanged in mice exposed to LPS/D-Gal. Post-insult treatment with the AMPK activator A-769662 further increased the phosphorylation levels of AMPK and JNK, enhanced hepatocyte apoptosis and deteriorated liver injury, all of these effects could be reversed by co-administration of the AMPK inhibitor or JNK inhibitor. Interestingly, post-insult treatment with the AMPK inhibitor also resulted in beneficial outcomes. These data suggested that AMPK might be a late detrimental factor in LPS/D-Gal-induced hepatitis via potentiating JNK-dependent hepatocyte apoptosis and AMPK might become a pharmacological target for the intervention of fulminant hepatitis.