Abstract
A S L D A b st ra ct s further investigated whether activation of ALDH2 using the novel small molecule, Alda-1, attenuates mitochondrial dysfunction and liver injury after chronic ethanol exposure. Methods: Male C57BL/6 mice were fed a liquid diet containing 27% of calories from ethanol and injected with Alda-1 (50 mg/kg, i.p. daily) or vehicle for 3 weeks. Results: Adducts of malondialdehyde-acetaldehyde (MAA) formed from acetaldehyde increased in liver tissue after ethanol feeding, which Alda-1 decreased, consistent with enhancement of acetaldehyde degradation by Alda-1. Chronic ethanol consumption caused mitochondrial depolarization in ~40% of hepatocytes as revealed by intravital confocal/multiphoton microscopy, which Alda-1 partially prevented. Ethanol increased serum ALT from 30 U/L to ~110 U/L, which Alda-1 treatment decreased to 53 U/L. Chronic ethanol exposure caused hepatic steatosis, as indicated by wide-spread Oil-Red-O-stained fat droplets and increased hepatic triglycerides. Alda-1 treatment decreased fat droplets and triglycerides in the liver after ethanol consumption. By H&E histology, hepatocyte ballooning, accumulation of macroand microvesicular fat droplets, necrosis, apoptosis and white blood cell infiltration developed after chronic ethanol exposure. TUNEL-positive cells also increased in association with caspase3 activation, indicating apoptosis. Myeloperoxidase and F4/80 increased markedly in liver tissue, suggesting neutrophil and monocyte/macrophage infiltration. Alda-1 decreased these markers of cell death and inflammation. Conclusion: Chronic ethanol consumption causes mitochondrial dysfunction and steatohepatitis in vivo, at least in part, due to production of toxic acetaldehydes. Activation ofmitochondrial ALDH2 decreasesmitochondrial dysfunction and steatohepatitis and is a promising strategy to prevent/minimize liver injury from chronic ethanol exposure (NIAAA, NIDDK & Charleston Alcohol Research Center).
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