Zinc and Hepatocyte Nuclear Factor-4 in Alcohol-Induced Intestinal Barrier Dysfunction

Abstract

Zinc is an essential micronutrient and plays an important role in maintaining intestinal epithelial integrity. Increasing evidence support that zinc homeostasis has significant impact on the intestinal barrier via regulation of epithelial tight junction proteins. Intestinal barrier plays a critical role in the prevention of endotoxin penetration from the intestinal lumen to the blood. Disruption of the intestinal barrier leads to elevation of blood endotoxin level, namely endotoxemia. Endotoxemia may lead to proinflammatory cytokine production and inflammation, thereby being an etiological factor in the pathogenesis of alcoholic liver disease (ALD). Recent studies demonstrated that oxidative stress and zinc deficiency correlate well with alcohol-induced gut leakiness. Alcohol exposure induces oxidative stress which, in turn, releases zinc from proteins. Hepatocyte nuclear factor-4 (HNF-4 ) is a zinc finger transcription factor which abundantly distributes in the intestine, particularly the distal intestine. Inactivation of HNF-4 correlates well with alcohol-induced down- regulation of tight junction proteins. This review discusses mechanisms involved in alcohol-induced intestinal epithelial barrier disruption with emphasis on the relationship among oxidative stress, zinc deficiency, and HNF-4 inactivation.