PCBs worsen obesity/metabolic syndrome through 'toxic metabolic endotoxemia'

Summary

Principal Investigator: MATTHEW C CAVE
Abstract: DESCRIPTION (provided by applicant): 68% of US adults are either overweight or obese, and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs), which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago, PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a "leaky gut" to disrupt the gut:liver:adipose axis. Subsequently, intestinal-derived bacterial products enter the bloodstream causing inflammation, liver disease and contribute to obesity and diabetes. We call this problem "toxic-metabolic endotoxemia". We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes;and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to:!! 1) Determine in mice, mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors, perturb the gut:liver:adipose axis, and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.
Funding Period: 2012-05-08 - 2017-02-28
more information: NIH RePORT

Top Publications

  1. pmc Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers
    Matt Cave
    Department of Medicine Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY 40202, USA
    J Occup Environ Med 53:1128-33. 2011
  2. ncbi Zinc and liver disease
    Mohammad K Mohammad
    University of Louisville, Louisville, KY, USA
    Nutr Clin Pract 27:8-20. 2012
  3. pmc Metabolomic analysis of the effects of polychlorinated biphenyls in nonalcoholic fatty liver disease
    Xue Shi
    Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, USA
    J Proteome Res 11:3805-15. 2012
  4. ncbi Toxicant-associated steatohepatitis
    Banrida Wahlang
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
    Toxicol Pathol 41:343-60. 2013
  5. pmc Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice
    Banrida Wahlang
    Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
    J Nutr Biochem 24:1587-95. 2013

Detail Information

Publications5

  1. pmc Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers
    Matt Cave
    Department of Medicine Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY 40202, USA
    J Occup Environ Med 53:1128-33. 2011
    ..The purpose of this study is to determine the prevalence of CK18 elevation in elastomer/polymer workers exposed to acrylonitrile, 1,3-butadiene, and styrene...
  2. ncbi Zinc and liver disease
    Mohammad K Mohammad
    University of Louisville, Louisville, KY, USA
    Nutr Clin Pract 27:8-20. 2012
    ..The dose of zinc used for treatment of liver disease is usually 50 mg of elemental zinc taken with a meal to decrease the potential side effect of nausea...
  3. pmc Metabolomic analysis of the effects of polychlorinated biphenyls in nonalcoholic fatty liver disease
    Xue Shi
    Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, USA
    J Proteome Res 11:3805-15. 2012
    ..Antioxidant depletion is likely to be an important consequence of this interaction, as this metabolic disturbance has previously been implicated in obesity and NAFLD...
  4. ncbi Toxicant-associated steatohepatitis
    Banrida Wahlang
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
    Toxicol Pathol 41:343-60. 2013
    ..This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD...
  5. pmc Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice
    Banrida Wahlang
    Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
    J Nutr Biochem 24:1587-95. 2013
    ..Amongst PCB congeners, PCB 153 has the highest serum level. PCBs have been dose-dependently associated with obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in epidemiological studies...

Research Grants30

  1. 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. ..
  2. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  3. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  4. Effects of recombinant human leptin in nonalcoholic fatty liver disease (NAFLD)
    Elif Arioglu Oral; Fiscal Year: 2013
    ..If our hypotheses are correct, 20% of people with fatty liver disease (those with relative leptin deficiency) may derive direct clinical benefit from implications of our research. ..
  5. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  6. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  7. Regulation of Bile Acid Synthesis by Nuclear Receptors
    John Y L Chiang; Fiscal Year: 2013
    ..The long-term objectives of this research are to elucidate the molecular mechanism of regulation of CYP7A1 and bile acid metabolism, and pathogenesis and treatment of metabolic diseases such as fatty liver disease, diabetes and obesity. ..
  8. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  9. Role of stearoyl CoA desaturase-1 in TLR5 KO mice colitis and metabolic syndrome
    Matam Vijay Kumar; Fiscal Year: 2013
    ..Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify whether SCD-1 can be targeted to prevent colitis and metabolic diseases ! ..