beta-Lapachone alleviates alcoholic fatty liver disease in rats

Abstract

Alcohol-induced liver injury is the most common liver disease in which fatty acid metabolism is altered. It is thought that altered NAD(+)/NADH redox potential by alcohol in the liver causes fatty liver by inhibiting fatty acid oxidation and the activity of tricarboxylic acid cycle reactions. beta-Lapachone (beta L), a naturally occurring quinone, has been shown to stimulate fatty acid oxidation in an obese mouse model by activating adenosine monophosphate-activated protein kinase (AMPK). In this report, we clearly show that beta L reduced alcohol-induced hepatic steatosis and induced fatty acid oxidizing capacity in ethanol-fed rats. beta L treatment markedly decreased hepatic lipids while serum levels of lipids and lipoproteins were increased in rats fed ethanol-containing liquid diets with beta L administration. Furthermore, inhibition of lipolysis, enhancement of lipid mobilization to mitochondria and upregulation of mitochondrial beta-oxidation activity in the soleus muscle were observed in ethanol/beta L-treated animals compared to the ethanol-fed rats. In addition, the activity of alcohol dehydrogenase, but not aldehyde dehydrogenase, was significantly increased in rats fed beta L diets. beta L-mediated modulation of NAD+/NADH ratio led to the activation of AMPK signaling in these animals. Conclusion: Our results suggest that improvement of fatty liver by beta L administration is mediated by the upregulation of apoB100 synthesis and lipid mobilization from the liver as well as the direct involvement of beta L on NAD(+)/NADH ratio changes, resulting in the activation of AMPK signaling and PPAR alpha-mediated beta-oxidation. Therefore, beta L-mediated alteration of NAD(+)/NADH redox potential may be of potential therapeutic benefit in the clinical setting. (C) 2013 Elsevier Inc. All rights reserved.