Metabolic syndrome (MetS) is a multi-factorial disease that can develop from steatosis and contribute to the etiology of non-alcoholic fatty liver disease, cardiovascular disease, diabetes, and hepatocellular carcinoma. It is characterized by dyslipidemia, obesity, and increased hepatic triglycerides (TRGs) due to the accumulation of lipids from adipose lipolysis and increased absorption of dietary fat. 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds have been implicated in MetS development, as well as diabetes and dyslipidemia. TCDD induces hepatic steatosis by increasing fatty acid and TRG levels, inhibiting adipocyte proliferation, decreasing glucose transport, and disrupting lipid and carbohydrate metabolism and transport. In this proposal, we will investigate aryl hydrocarbon receptor (AhR)-mediated systemic alterations in lipid metabolism and transport that contribute to hepatic steatosis, the initial step in Mets development. More specifically, we will test the hypothesis that AhR-mediates intestinal, circulatory and hepatic lipid uptake, metabolism, and transport effects leading to hepatic steatosis that involve dioxin response element (DRE)-independent mechanisms. Our preliminary data suggest that AhR-mediated changes in lipid transport and metabolism involve non-canonical AhR-mediated gene expression.
Our specific aims will examine (1) dietary fat as a lipid source in AhR-mediated hepatic steatosis, (2) AhR peroxisome proliferator activated receptor (PPAR) signaling pathways interactions that disrupt lipid transport and metabolism gene expression contributing to hepatic fat accumulation, (3) AhR/COUP-TF-mediated inhibition of hepatocyte nuclear factor 4 alpha (HNF4a)-regulated lipid transport and metabolism gene expression, (4) lipid composition and transport gene expression in human and mouse primary hepatocytes, and (5) the effects of AhR-ligands on serum lipid levels and composition in mice. These studies will not only elucidate the AhR-mediated mechanisms involved in steatosis, but also provide further evidence that TCDD and related compound exposure plays a contributory role in the etiology of MetS and its related diseases using non-canonical DRE-independent mechanisms. These studies also complement Project 4 (Hashsham) which examines effects on choline uptake and metabolism in the intestine and liver. In addition, collaborations with Project 2 (Thomas) and Research Support Core A (Zhang/Conolly) will identify other genetic traits relevant to AhR-mediated dyslipidemia and provide data to support the development of bioenergetic computational models regulated by the AhR, respectively.

Public Health Relevance

Mets incidence is approaching pandemic proportions. Although genetics, sedentary lifestyle and increased caloric intake are significant factors, accumulating evidence suggests TCDD and related compounds have an underappreciated role in disease development. These studies will investigate the role of AhR in TCDD elicited steatosis, the initial step in the etiology of MetS. In addition to elucidating mechanisms, our results will support public health policies to reduce TCDD and related compound exposure, and establish the AhR as a potential therapeutic target for the treatment of MetS and its associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004911-23
Application #
8695353
Study Section
Special Emphasis Panel (ZES1-LWJ-D)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
23
Fiscal Year
2014
Total Cost
$243,027
Indirect Cost
$78,382
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Hwang, Hye Jin; Dornbos, Peter; Steidemann, Michelle et al. (2016) Mitochondrial-targeted aryl hydrocarbon receptor and the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on cellular respiration and the mitochondrial proteome. Toxicol Appl Pharmacol 304:121-32
Hwang, Hye Jin; Dornbos, Peter; LaPres, John J (2016) Data on AHR-dependent changes in the mitochondrial proteome in response to ,3,7,8-tetrachlorodibenzo-p-dioxin. Data Brief 8:191-5
Stedtfeld, Robert D; Williams, Maggie R; Fakher, Umama et al. (2016) Antimicrobial resistance dashboard application for mapping environmental occurrence and resistant pathogens. FEMS Microbiol Ecol 92:
Kovalova, Natalia; Manzan, Maria; Crawford, Robert et al. (2016) Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells. Toxicol Appl Pharmacol 309:15-23
Tian, Haoting; Gao, Juan; Li, Hui et al. (2016) Complete Defluorination of Perfluorinated Compounds by Hydrated Electrons Generated from 3-Indole-acetic-acid in Organomodified Montmorillonite. Sci Rep 6:32949
Phadnis-Moghe, Ashwini S; Li, Jinpeng; Crawford, Robert B et al. (2016) SHP-1 is directly activated by the aryl hydrocarbon receptor and regulates BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol 310:41-50
Nault, Rance; Fader, Kelly A; Kirby, Mathew P et al. (2016) Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. Toxicol Sci 149:358-71
Wang, Qiong; Fish, Jordan A; Gilman, Mariah et al. (2015) Xander: employing a novel method for efficient gene-targeted metagenomic assembly. Microbiome 3:32
Nault, Rance; Colbry, Dirk; Brandenberger, Christina et al. (2015) Development of a computational high-throughput tool for the quantitative examination of dose-dependent histological features. Toxicol Pathol 43:366-75
Liu, Cun; Gu, Cheng; Yu, Kai et al. (2015) Integrating structural and thermodynamic mechanisms for sorption of PCBs by montmorillonite. Environ Sci Technol 49:2796-805

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