Lipid‐derived aldehyde, acrolein, is a critical mediator of alcohol‐induced gut‐liver injury in alcoholic liver disease

Alcohol consumption can cause alcoholic liver disease (ALD). Chronic alcohol consumption causes a pro‐oxidant environment in the liver and increases hepatic lipid peroxidation. Acrolein (ACR) is the most reactive and toxic aldehyde generated through lipid peroxidation. ACR forms protein adducts and triggers endoplasmic reticulum (ER) stress and hepatocyte apoptosis, which are recognized etiologic factors in ALD. Moreover, recent evidence has established the critical role of the gut‐liver axis in ALD pathogenesis, wherein alcohol‐induced gut barrier dysfunction contributes to liver injury. This study investigates the pathogenic role of acrolein as a major mediator gut‐liver axis in ALD. Accumulation of ACR adducts was seen in response to alcohol consumption in mouse livers and intestines. Acrolein adduct accumulation correlated with hepatic steatosis, JNK activation, ER stress, apoptosis and liver injury. We used cultured hepatic and intestinal cells to examine the direct in vitro effects of acrolein exposure in comparison to alcohol exposure. Alcohol‐induced in vivo intestinal effects were mimicked by ACR in vitro in intestinal Caco2 cells; specifically, ACR down‐regulated tight junction proteins, resulting in disruption of TEER (transepithelial electrical resistance), and increased FD‐4 permeability. In vitro acrolein exposure in hepatic cells triggered ER stress and induced apoptotic cell death, indicating that acrolein may mediate the effects of alcohol. Notably, these effects were attenuated by acrolein scavengers suggesting their therapeutic potential in ALD.