Lipid‐derived aldehyde, acrolein, is a critical mediator of alcohol‐induced gut‐liver injury (653.14)

Abstract

Alcohol is the most socially accepted addictive drug which leads to alcoholic liver disease (ALD), a major cause of morbidity/mortality in the United States. Chronic alcohol consumption, commonly associated with cigarette smoking, causes a pro‐oxidant environment in the liver and increases lipid peroxidation. Acrolein (ACR) is the most reactive and hepatotoxic aldehyde metabolite generated via lipid peroxidation, and is a major component of cigarette smoke. This study investigates the pathogenic role of acrolein as a major mediator of intestinal barrier dysfunction and hepatic endoplasmic reticulum (ER) stress and injury, which are recognized etiologic factors in ALD.We examined hepatic and intestinal effects of acrolein and alcohol using in vitro (rat hepatic H4IIEC, and human intestinal epithelial Caco2 cells) and in vivo (C57/Bl6 mice ‐ chronic+binge alcohol feeding) models. ACR adducts accumulated in response to alcohol or ACR in mouse livers and intestines, and in cultured cells. This was accompanied by hepatic steatosis, activation of JNK, ER stress (upregulation of ATF3, ATF4, and pro‐apoptotic CHOP), mitochondrial disruption and apoptosis as seen by Cellomics. Notably, the cytotoxic effects of ACR and alcohol were attenuated by acrolein/aldehyde scavengers, and by an inhibitor of phosphodiesterase‐4 which regulates cellular cAMP. Alcohol‐induced in vivo intestinal effects (down‐regulation of tight junction proteins ZO‐1, occludin, and claudin, and barrier dysfunction) were mimicked by ACR in Caco2 cells. Our study demonstrates that acrolein is an important mediator of the hepatic and intestinal effects of alcohol consumption, and suggests a therapeutic potential for phosphodiesterase inhibitors and acrolein scavengers in ALD.Grant Funding Source: Supported by NIH, DOD and Veterans Administration