Dietary Fat in Ethanol-Induced Intestinal Barrier Dysfunction in ALD

Summary

Principal Investigator: Irina Kirpich
Abstract: DESCRIPTION (provided by applicant): This application will evaluate Gut-Liver and Diet-Alcohol interactions with respect to the critical role of intestinal barrier integrity/function in he development and progression of alcoholic liver disease (ALD). ALD remains one of the leading causes of liver diseases and a major cause of morbidity and mortality in the United States and worldwide. Why some heavy drinkers develop ALD and other are spared is unclear (we postulate dietary effects-see below). Gut-derived lipopolysaccharide (LPS) plays a crucial role in the development of ALD. Increased intestinal permeability resulting from the disruption of intestinal integrity is a major cause of alcohol-induced endotoxemia. Dietary fat is an important cofactor for the development of ALD. It has been shown that diets enriched in saturated fatty acids protect against alcohol-induced liver disease in rodents, whereas dietary polyunsaturated fatty acids (e.g. linoleic acid, LA) promote liver damage. Our working hypothesis is that dietary LA potentiates pro-oxidative and pro-inflammatory effects on intestinal epithelial cells with consequent NF-kB activation. These events lead to alterations of intestinal tight junctions through an MLCK-dependent mechanism and contribute to the ethanol-associated disruption of intestinal integrity. We hypothesize that the combined deleterious effects of LA and EtOH on intestinal barrier integrity occur through a common NF-kB-MLCK-mediated mechanism. Increased gut permeability leads to elevated blood endotoxemia and consequent liver injury. Thus, inhibition of MLCK will attenuate intestinal tight junction disruption, decrease gut leakines and blood endotoxemia, and attenuate ethanol/dietary linoleic acid induced liver damage. The Specific Aims of our application are: 1. To determine: a) if linoleic acid induces oxidative stress activates NF-kB and increases pro-inflammatory cytokine production in Caco-2 cells, an in vitro model of the intestinal epithelial barrier;b) if linoleic acid enhances ethanol- mediated disruptin of intestinal barrier integrity by deregulation and redistribution of the major tight junctions proteins through an NF-kB-MLCK-mediated mechanism, and if this effect is additive or synergistic. 2. To determine: a) whether dietary linoleic acid potentiates intestinal oxidative stress and promotes intestinal inflammation through NF-kB activation in an animal model of ALD;b) whether dietary linoleic acid-mediated intestinal inflammation contributes to ethanol-associated intestinal tight junction dysfunction through the MLCK-mediated mechanism in vivo;and c) if pharmacological inhibition/genetic deletion of MLCK can attenuate tight junction alterations, decrease gut permeability and blood endotoxemia, and consequently attenuate liver injury in a mouse model of ALD. Dietary modulation may represent a novel preventive/therapeutic approach in ALD, and MLCK could be a specific novel therapeutic target.
Funding Period: 2012-08-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease
    Irina A Kirpich
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Kentucky, USA
    Alcohol Clin Exp Res 36:835-46. 2012
  2. ncbi Probiotics in the treatment of the liver diseases
    Irina A Kirpich
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, KY 40202, USA
    J Am Coll Nutr 31:14-23. 2012
  3. pmc Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment
    Lara Bull-Otterson
    Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
    PLoS ONE 8:e53028. 2013
  4. pmc Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol
    Irina A Kirpich
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Alcohol 47:257-64. 2013
  5. pmc Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury
    Yuhua Wang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
    J Nutr Biochem 24:1609-15. 2013
  6. pmc Binge ethanol-induced HDAC3 down-regulates Cpt1α expression leading to hepatic steatosis and injury
    Irina Kirpich
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky University of Louisville Alcohol Research Center, Louisville, Kentucky
    Alcohol Clin Exp Res 37:1920-9. 2013

Detail Information

Publications6

  1. pmc The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease
    Irina A Kirpich
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Kentucky, USA
    Alcohol Clin Exp Res 36:835-46. 2012
    ..The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD...
  2. ncbi Probiotics in the treatment of the liver diseases
    Irina A Kirpich
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, KY 40202, USA
    J Am Coll Nutr 31:14-23. 2012
    ..The present review summarizes the recent studies highlighting the role of the intestinal microflora in the development of NAFLD and ALD and the potential efficacy of probiotics as a therapeutic strategy for liver diseases...
  3. pmc Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment
    Lara Bull-Otterson
    Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
    PLoS ONE 8:e53028. 2013
    ..Moreover, the altered bacterial communities of the gut may serve as significant therapeutic target for the prevention/treatment of chronic alcohol intake induced intestinal barrier dysfunction and liver disease...
  4. pmc Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol
    Irina A Kirpich
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Alcohol 47:257-64. 2013
    ..Therefore, dietary unsaturated fat (corn oil/LA enriched) is a significant contributing factor to EtOH-mediated intestinal inflammatory response and mucus layer alterations in rodents...
  5. pmc Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury
    Yuhua Wang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
    J Nutr Biochem 24:1609-15. 2013
    ..In conclusion, probiotic LGG treatment reduced alcohol-induced hepatic inflammation by attenuation of TNFα production via inhibition of TLR4- and TLR5-mediated endotoxin activation. ..
  6. pmc Binge ethanol-induced HDAC3 down-regulates Cpt1α expression leading to hepatic steatosis and injury
    Irina Kirpich
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky University of Louisville Alcohol Research Center, Louisville, Kentucky
    Alcohol Clin Exp Res 37:1920-9. 2013
    ..Hence, in the present work, we specifically examined the mechanistic role of HDAC3 in the development of hepatic steatosis occurring in response to binge alcohol administration...

Research Grants30

  1. Probiotics and HIF signaling in Alcoholic Liver Disease
    Wenke Feng; Fiscal Year: 2013
    ..This study will have a major impact on the development of new therapeutic targets for the prevention and treatment of ALD. ..
  2. Homocysteine, Adiponectin, and Alcoholic Liver Disease
    Zhenyuan Song; Fiscal Year: 2013
    ..We will use the state-of-the-art technologies to investigate this clinically relevant process. ..
  3. Synergistic actions by multiple Toll-like receptors in alcoholic liver disease
    Ekihiro Seki; Fiscal Year: 2013
    ..The results from this study will provide the potential targeting for the therapy of alcohol-induced organ pathogenesis including steatohepatitis and brain injury. ..
  4. Alcohol, Proteasome Dysfunction in Liver Injury
    Craig J McClain; Fiscal Year: 2013
    ....
  5. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  6. Circadian Desynchrony in Alcohol Induced Gut Leakiness
    Garth R Swanson; Fiscal Year: 2013
    ..This study will reveal significant new information regarding the interaction of alcohol and circadian biology in ALD pathogenesis that could be used to improve prevention and treatment of ALD. ..
  7. Microbiome as Therapeutic Target in Alcoholic Hepatitis
    BERND G SCHNABL; Fiscal Year: 2013
    ..Eventually this approach might lead to new therapeutic targets for patients with alcoholic hepatitis. ..
  8. Zinc supplementation in alcoholic cirrhosis
    MATTHEW C CAVE; Fiscal Year: 2013
    ..We will perform a randomized, double blind, placebo-controlled, "drop in", mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. ..
  9. Functional characters of non-coding RNAs in alcoholic liver injury
    Fanyin Meng; Fiscal Year: 2013
    ..abstract_text> ..
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. Microbiome and intestinal innate immune response in alcoholic liver disease
    BERND G SCHNABL; Fiscal Year: 2013
    ..Eventually this approach might lead to new therapeutic targets for patients with alcoholic liver disease. ..
  12. MECHANISM OF ENDOTOXIN ABSORPTION IN ALCOHOLISM
    Radhakrishna Rao; Fiscal Year: 2013
    ..The outcome of these studies is expected to provide knowledge to develop new therapies in the treatment of alcoholic liver disease and alcohol-induced tissue injury in pancreas and lung. ..
  13. TNF Alpha and Recovery from Alchoholic Liver Injury
    ANNA MAE ELIZABETH DIEHL; Fiscal Year: 2013
    ..This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease. ..
  14. Altered Lipid Droplet Trafficking: Role in Alcoholic Fatty Liver Disease
    MARK A MC NIVEN; Fiscal Year: 2013
    ....
  15. Cyclic AMP, Cytokine Modulation and Alcoholic Liver Disease
    Craig J McClain; Fiscal Year: 2013
    ..The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism, and our overall goal is the development of novel therapeutic interventions. ..