Binge Alcohol Intake After Hypergravity Stress Sustainably Decreases AMPK and Transcription Factors Necessary for Hepatocyte Survival.

Abstract

Binge alcohol consumption elicits mitochondrial dysfunction in hepatocytes. An understanding of the effect of ethanol (EtOH) exposure after hypergravity stress on liver function may assist in the implementation of pathophysiological countermeasures for aerospace missions. This study investigated whether a combination of hypergravity stress and binge alcohol intake has a detrimental effect on AMP-activated protein kinase (AMPK) and other molecules necessary for hepatocyte survival. The mice were orally administered a single dose of EtOH (5g/kg body weight, 20% EtOH) immediately after a load to +9Gz hypergravity for 1hour using a small animal centrifuge and sacrificed 24hours after treatment. For the multiple-dose model, 3 consecutive daily treatments were carried out. Immunoblottings were carried out on liver homogenates. Binge alcohol intake in mice immediately after a 1-hour exposure to a +9Gz hypergravity load repressed hepatic Akt and PARP-1 levels at 24hours posttreatment. Moreover, it sustainably diminished the level of AMPKα, a key regulator of energy metabolism, as compared to each individual treatment. Similarly, the combination of alcohol and hypergravity suppressed the levels of STAT3, FOXO1/3, C/EBPβ, and CREB, transcription factors necessary for cell survival. Similar changes were not detected after 3 consecutive daily combinatorial treatments, indicating that repetitive training with hypergravity loads provides hepatoprotective effects in a binge alcohol model. These results show that binge alcohol exposure in mice immediately following a +9Gz hypergravity stress persistently decreased AMPKα and other key molecules required for hepatocyte survival, and these changes may be reversed by repetitive hypergravity loads.