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.
Highlights
AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that has central roles in maintaining energy homeostasis.[1,2] AMPK is composed of the catalytic α subunit and the regulatory β/γ subunits.[3]
The present study found that the enhanced Jun N-terminal kinase (JNK) phosphorylation, increased hepatocyte apoptosis and deteriorated liver injury in AMPK activator-treated mice were reversed by JNK inhibition (Figures 6a-e)
We found that AMPK was activated in mice with LPS/DGal-induced fulminant hepatitis
Summary
AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that has central roles in maintaining energy homeostasis.[1,2] AMPK is composed of the catalytic α subunit and the regulatory β/γ subunits.[3]. Since the liver is one of the metabolic centers with complex functions in nutrition and energy metabolism, the physiological roles of AMPK in the liver have been intensively studied.[8] These studies have found that AMPK promotes glucose oxidation but suppresses gluconeogenesis in the liver via direct phosphorylation and transcriptional modulation of key metabolic enzymes.[9,10] In addition, AMPK controls the metabolism of fats and proteins in the liver.[10] the important physiological functions of AMPK have been well studied, the pathological significance of AMPK in liver disorders remains largely unknown. LPS/D-Gal-induced liver injury in mice is a well-established experimental hepatitis model.[13] The hepatocyte damage in this model largely depends on the early production of detrimental inflammatory mediators such as tumor necrosis factor alpha (TNF-α), and these deleterious factors might induce massive hepatocyte apoptosis and lethal outcomes at the late stage.[14,15] In the present study, the phosphorylation status of AMPK was determined. Received 14.9.16; revised 19.1.17; accepted 24.1.17; Edited by M Agostini inhibitor, and the degree of inflammation and apoptosis and the potential underlying mechanism were evaluated
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