Evidence from clinical and experimental studies indicates that elevated intestinal permeability to endotoxins and the resulting endotoxemia play a crucial role in the pathogenesis of alcoholic liver disease. Our studies conducted so far have shown that acetaldehyde, the metabolic product of ethanol, is accumulated in the intestine of alcoholics and disrupts the intestinal epithelial barrier function and increases the permeability to endotoxins. The mechanism of this acetaldehyde-induced disruption of epithelial barrier function involves inhibition of a protein tyrosine phosphatase, PTP1B, tyrosine phosphorylation of junctional proteins, disruption of the interactions among the junctional proteins (that determine the barrier function), and loss of integrity of the junctional complexes. Our preliminary studies also indicated that epidermal growth factor (EGF) and L-glutamine prevent acetaldehyde-mediated increase in permeability to endotoxins. On the basis of our results it is further hypothesized that: a) acetaldehyde-induced phosphorylation of PTP1B and beta-catenin disrupts E-Cadherin-beta-Catenin-PTP1B complex, b) EGF and L-glutamine prevent acetaldehyde induced disruption of junctions by PLCgamma and MAP kinase mediated signals, and c) L-glutamine prevents acetaldehyde-induced disruption of junctions by EGF receptor-dependent mechanism. Using a cell culture model of the intestinal epithelium and human colonic biopsies we will to determine that: 1) interaction between E-cadherin and PTP1B is reduced by Thr-phosphorylation of PTP1B, 2) phosphorylation of beta-catenin on tyrosine residues prevents its binding to E-cadherin, 3) mutation of specific threonine residues on PTP1B and tyrosine residues in beta-catenin prevents the acetaldehyde-induced disruption of junctions, 4) EGF and glutamine prevent acetaldehyde-induced phosphorylation of PTP1B and beta-catenin, and disruption of E-cadherin/beta-catenin/PTP1B complex, 5) PLCgamma and MAP kinase signaling pathways mediate EGF- and glutamine-induced prevention of phosphorylation of PTP1B and beta-catenin, and disruption of E-cadherin/beta-catenin/PTP1B complex, 6) L-glutamine prevents acetaldehyde-induced phosphorylation of PTP1B and beta-catenin, and disruption of E-cadherin/beta-catenin/PTP1B complex by EGF receptor-dependent mechanism, 7) EGF receptor activation is involved in glutamine-mediated prevention of acetaldehyde-induced disruption of AJ and TJ, 9) glutamine prevents acetaldehyde-induced disruption of AJ and TJ by Src kinase dependent mechanism, and 10) EGF receptor activation by glutamine is mediated by extra cellular release of metalloproteinase and TGFalpha. Information derived from this study will expand our understanding of acetaldehyde-mediated injury in intestinal epithelium and endotoxin absorption in alcoholics. The studies on the protection of barrier function by epidermal growth factor and L-glutamine have the potential to provide the basis for the development of preventive and therapeutic strategies for alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012307-07
Application #
7118207
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Purohit, Vishnu
Project Start
2000-05-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
7
Fiscal Year
2006
Total Cost
$285,138
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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