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

Public Health Relevance

Alcohol intoxication causes multiple organ injury, but FDA-approved effective therapy is not available. Alcohol metabolism generates aldehydes which are cytotoxic. Aldehyde generation in the intestine disrupts gut barrier, leading to endotoxemia which triggers inflammation. Liver dysfunction in aldehyde clearance will cause aldehyde accumulation in the liver and blood, leading to multiple organ injury. This project will define the role of aldehyde as a systemic factor in mediating alcohol-induced tissue damage at the gut-liver-brain axis. The proposed research will not only advance our knowledge on alcohol-induced pathogenesis, but also suggest the removal of aldehydes as a potential therapeutic strategy for treatment of alcohol-induced diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020212-03
Application #
8317630
Study Section
Special Emphasis Panel (ZAA1-JJ (01))
Program Officer
Brooks, Pj
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$471,603
Indirect Cost
$133,536
Name
University of North Carolina Greensboro
Department
Nutrition
Type
Schools of Arts and Sciences
DUNS #
616152567
City
Greensboro
State
NC
Country
United States
Zip Code
27402
Zhang, Wenliang; Zhong, Wei; Sun, Qian et al. (2018) Adipose-specific lipin1 overexpression in mice protects against alcohol-induced liver injury. Sci Rep 8:408
Hao, Liuyi; Sun, Qian; Zhong, Wei et al. (2018) Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease. Redox Biol 14:626-636
Zhou, Zhanxiang; Zhong, Wei (2017) Targeting the gut barrier for the treatment of alcoholic liver disease. Liver Res 1:197-207
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2017) Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function. Biochim Biophys Acta Gen Subj 1861:2912-2921
Sun, Qian; Zhong, Wei; Zhang, Wenliang et al. (2016) Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency. Am J Physiol Gastrointest Liver Physiol 310:G205-14
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Wang, Xiaoning; Xie, Guoxiang; Zhao, Aihua et al. (2016) Serum Bile Acids Are Associated with Pathological Progression of Hepatitis B-Induced Cirrhosis. J Proteome Res 15:1126-34
Zhang, Wenliang; Sun, Qian; Zhong, Wei et al. (2016) Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice. Alcohol Clin Exp Res 40:988-99
Dong, Daoyin; Zhong, Wei; Sun, Qian et al. (2016) Oxidative products from alcohol metabolism differentially modulate pro-inflammatory cytokine expression in Kupffer cells and hepatocytes. Cytokine 85:109-19
Zhong, Wei; Li, Qiong; Sun, Qian et al. (2015) Preventing Gut Leakiness and Endotoxemia Contributes to the Protective Effect of Zinc on Alcohol-Induced Steatohepatitis in Rats. J Nutr 145:2690-8

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