Abstract
Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation.
Highlights
Alcohol abuse causes alcoholic liver disease (ALD), but the mechanisms of disease pathogenesis have not been well defined
The objective of the present study was to determine whether dietary nicotinic acid supplementation could alleviate alcohol-induced endotoxemia and endotoxin signaling in the liver
The present study demonstrates that dietary nicotinic acid supplementation alleviated alcohol-induced endotoxemia and endotoxin signaling in the liver
Summary
Alcohol abuse causes alcoholic liver disease (ALD), but the mechanisms of disease pathogenesis have not been well defined. A clinical study found that intestinal permeability was elevated only in alcoholics with liver disease but in alcoholics without liver disease [5], which suggests that gut leakiness may be a key co-factor in triggering the development of ALD. Increasing evidence suggest that the elevation of blood endotoxin level, namely endotoxemia, plays a critical role in the pathogenesis of ALD [6,7,8]. Clinical studies have shown a positive correlation between the blood endotoxin levels and hepatic cytokine levels as well as the severity of liver damage [10,11,12]. Neutralization of circulating endotoxin has shown to attenuate alcohol-induced liver injury [13], suggesting a cause-effect relationship between endotoxemia and the pathogenesis of ALD
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