The pathogenesis of alcoholic liver disease involves elevated plasma endotoxin and endotoxin mediated liver injury. Evidence from clinical and experimental studies suggests that elevated endotoxin level in alcoholism involves overgrowth of endotoxin producing bacteria and increased intestinal absorption of endotoxin. The investigators recently demonstrated that acetaldehyde the oxidative product of ethanol, known to be generated in the intestine, increases paracellular permeability in Caco-2 cell monolayers, an intestinal epithelial model. The acetaldehyde increase in permeability is mediated by a tyrosine kinase dependent mechanism and is associated with an inhibition of protein tyrosine phosphatase (PTPase) and increased protein tyrosine phosphorylation. The acetaldehyde effects on permeability was inhibited by L-glutamine, an amino acid considered for its therapeutic benefits in various gastrointestinal disorders. On the basis of preliminary results it is hypothesized that: 1) acetaldehyde dissociates protein complexes at the epithelial junctions by inducing tyrosine phosphorylation of b-catenin by regulating PTP1B (a PTPase), and 2) L-glutamine prevents acetaldehyde-induced increase in permeability by blocking the ability of acetaldehyde to inhibit PTP1B and increased tyrosine phosphorylation of b-catenin. Using the above mentioned model of intestinal epithelia, the investigators propose to determine: a) If acetaldehyde induces a dissociation of occludin/Z0-1 and E-Cadherin/b-catenin complexes. b) Whether acetaldehyde induces phosphorylation of b-catenin and specific tyrosine residues. c) Whether acetaldehyde inhibits PTP1B. d) If over expression of PTP1B delays acetaldehyde induced permeability and expression of phosphatase inactive PTP1B mutants decreases permeability, and e) If L-glutamine prevents acetaldehyde inhibition of PTP1B tyrosine phosphorylation of b-catenin and dissociation of E-cadherin/b-catenin complex. The information derived from these studies has the potential to expand our understanding of alcohol mediated increase in endotoxin absorption by identifying some of the mechanisms of acetaldehyde induced disruption of paracellular junctions and protection by L-glutamine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012307-05
Application #
6629497
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
5
Fiscal Year
2003
Total Cost
$213,000
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Meena, Avtar S; Shukla, Pradeep K; Sheth, Parimal et al. (2018) EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced gut barrier dysfunction and liver injury. J Nutr Biochem 64:128-143
Shukla, Pradeep K; Meena, Avtar S; Rao, Rupa et al. (2018) Deletion of TLR-4 attenuates fetal alcohol exposure-induced gene expression and social interaction deficits. Alcohol 73:73-78
Shukla, Pradeep K; Meena, Avtar S; Rao, Vaishnavi et al. (2018) Human Defensin-5 Blocks Ethanol and Colitis-Induced Dysbiosis, Tight Junction Disruption and Inflammation in Mouse Intestine. Sci Rep 8:16241
Shukla, Pradeep K; Meena, Avtar S; Manda, Bhargavi et al. (2018) Lactobacillus plantarum prevents and mitigates alcohol-induced disruption of colonic epithelial tight junctions, endotoxemia, and liver damage by an EGF receptor-dependent mechanism. FASEB J :fj201800351R
Manda, Bhargavi; Mir, Hina; Gangwar, Ruchika et al. (2018) Phosphorylation hotspot in the C-terminal domain of occludin regulates the dynamics of epithelial junctional complexes. J Cell Sci 131:
Gangwar, Ruchika; Meena, Avtar S; Shukla, Pradeep K et al. (2017) Calcium-mediated oxidative stress: a common mechanism in tight junction disruption by different types of cellular stress. Biochem J 474:731-749
Chaudhry, Kamaljit K; Shukla, Pradeep K; Mir, Hina et al. (2016) Glutamine supplementation attenuates ethanol-induced disruption of apical junctional complexes in colonic epithelium and ameliorates gut barrier dysfunction and fatty liver in mice. J Nutr Biochem 27:16-26
Samak, Geetha; Gangwar, Ruchika; Meena, Avtar S et al. (2016) Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers. Sci Rep 6:38899
Shukla, Pradeep K; Chaudhry, Kamaljit K; Mir, Hina et al. (2016) Chronic ethanol feeding promotes azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis potentially by enhancing mucosal inflammation. BMC Cancer 16:189
Mir, Hina; Meena, Avtar S; Chaudhry, Kamaljit K et al. (2016) Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice. Biochim Biophys Acta 1860:765-74

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