Aldehydes in Alcohol-Induced Organ Injury

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DESCRIPTION (provided by applicant): Alcohol consumption exerts toxic effects on the body with liver and brain as the major target organs. Recent studies suggest that alcohol-induced organ injury may involve organ-organ interactions. The most well-known mechanism underlying organ-organ interactions is gut-generated endotoxin (lipopolysaccharide, LPS) signal. Alcohol consumption causes gut barrier disruption, leading to endotoxemia, which, in turn, causes tissue injury at the liver-brain axis by stimulating cytokine production. Aldehyde generation is a feature of alcohol intoxication. While alcohol metabolism generates acetaldehyde, lipid peroxidation produces lipid aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Accumulation of aldehydes has been detected in intestinal contents, liver, blood and brain after alcohol intoxication. Aldehydes are cytotoxic, and may mediate alcohol actions at the gut-liver-brain axis. First, acetaldehyde generation from the gut microflora critically mediate alcohol-induced gut barrier disruption and generation of LPS signal. Second, aldehydes generated from the liver have shown to mediate alcohol-induced liver injury by inactivating proteins. Third, liver dysfunction in aldehyde clearance results in systemic aldehyde elevation, which may act as a systemic factor and mediate alcohol-induced brain damage. Aldehydes can be detoxified primarily by ALDH in the liver, however, our studies showed that mitochondrial ALDH (ALDH2) was not up-regulated in the liver despite aldehyde accumulation after chronic alcohol exposure. We also found that zinc supplementation attenuated alcohol-induced liver injury in association with up-regulation of ALDH2. Over-expression of ALDH2 has been shown to attenuate mitochondrial and endoplasmic reticulum (ER) stress, thereby preventing alcohol-induced organs injury including liver and brain. This project will test our hypothesis that aldehydes critically mediate alcohol-induced cytotoxicity at the gut-liver-brain axis, thereby being a systemic factor in alcohol-induced pathogenesis. Aim 1 is to define the role of microbiota aldehyde generation in alcohol-induced gut barrier disruption and generation of LPS signal. Effects of gut luminal aldehydes on gut tight junctions, blood LPS and liver-brain injury will be determined. Metabolic alterations in the gut luminal contents and epithelium will also be measured. Aim 2 is to determine the significance of hepatic aldehyde generation in alcohol-induced liver injury. Effects of aldehydes on hepatic lipid homeostasis and pro-inflammatory cytokine production will be determined. Interaction between aldehydes and LPS in pro-inflammatory cytokine production will also be measured. Mechanistic link of aldehydes with alcohol-induced metabolomic and proteomic alterations in the liver will be identified. Aim 3 is to determine the significance of liver-generated aldehyde signal in alcohol-induced brain injury. The link between liver dysfunction and systemic aldehyde elevation will be defined. The role of liver- generated aldehyde signal in alcohol-induced brain injury will be determined. Aim 4 is to explore the molecular mechanism of aldehyde toxicity and aldehyde removal therapies. Formation of aldehyde-protein adducts at the gut-liver-brain axis will be identified. Effects of ALDH2-recombinant L. acidophilus, zinc and resveratrol on aldehyde clearance and alcohol-induced organ injury will be determined. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page