Air pollution is a sustained problem of public health for the general population, especially for those that live in areas of intensive traffic or industrial activity. Epidemiological study and clinical observation have confirmed a link between inhaled air particulate matter (PM) and susceptibility to metabolic diseases. However, a precise understanding of molecular and cellular basis that drives air pollution-associated pathogenesis remains elusive. Recently we have accumulated provocative preliminary information that exposure to environmentally relevant air PM in fine ranges (diameter <2.5 ?m, PM2.5) induces endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR) in the mouse liver. Activation of the UPR signaling by ambient PM2.5 relies on reactive oxygen species and calcium signals. Furthermore, PM2.5-induced ER stress response is correlated with altered expression of key hepatic lipid regulators including peroxisome proliferator-activated receptor ? (PPAR?) and paraoxonase 1 (PON-1), abnormal hepatic lipid droplet accumulation, as well as impaired glucose/insulin homeostasis in obese animals. These observations lead to a novel hypothesis that ER stress response may be crucial for ambient PM2.5 to elicit its toxic effect that causes hepatic lipid dysregulation and subsequent metabolic disorders. In this application, we will use a """"""""real world"""""""" PM exposure system to recapitulate personal, chronic exposure to environmental relevant PM2.5 with animal models. Through this exposure system, molecular and cellular approaches, as well as pharmacologic tools, we will investigate the mechanisms by which ambient PM2.5 induces ER stress and the UPR activation that leads to dysregulation of hepatic lipid metabolism. Specifically, in Aim 1, we will expose C57BL/6J mice to concentrated PM2.5 along or in combination with a high-fat diet and then characterize ER stress and the UPR signaling pathways in the liver and other tissues.
In Aim 2, we will investigate the molecular basis for PM2.5-induced ER stress response in promoting dysregulation of hepatic lipid metabolism. We will also evaluate whether PM2.5-induced stress represents a """"""""hit"""""""" that triggers non-alcoholic fatty liver disease (NAFLD) in obese animals. The proposed studies are anticipated to reveal an unprecedented link between PM2.5 exposure and ER stress. The findings will not only contribute to a better understanding of the molecular and cellular mechanisms underlying airborne PM- induced pathogenesis, but will also have high impact on the medical care from the prevention to treatment of metabolic diseases associated with air pollution.

Public Health Relevance

Air pollution is a sustained problem of public health for the general population in urban areas, especially for those that live in areas of intensive traffic or industrial activity. Air particulate matter (PM) elicits its toxic effects on dysregulation of liver lipid metabolism through activating endoplasmic reticulum (ER) stress response. The proposed studies will not only be critical for a better understanding of the molecular and cellular basis by which air PM drives disease pathogenesis, but will also provide valuable information for the prevention and treatment of air pollution-associated systemic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES017829-02
Application #
8109851
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Shreffler, Carol K
Project Start
2010-07-12
Project End
2013-09-30
Budget Start
2011-07-01
Budget End
2013-09-30
Support Year
2
Fiscal Year
2011
Total Cost
$239,086
Indirect Cost
Name
Wayne State University
Department
Genetics
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Wang, Jie-Mei; Qiu, Yining; Yang, Zeng-Quan et al. (2017) Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs. Diabetes 66:177-192
Hou, Xia; Yang, Zhao; Zhang, Kezhong et al. (2017) SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6. Biochem Biophys Res Commun 494:446-451
Kim, Hyunbae; Zheng, Ze; Walker, Paul D et al. (2017) CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis. Mol Cell Biol 37:
Qiu, Yining; Zheng, Ze; Kim, Hyunbae et al. (2017) Inhalation Exposure to PM2.5 Counteracts Hepatic Steatosis in Mice Fed High-fat Diet by Stimulating Hepatic Autophagy. Sci Rep 7:16286
Wang, Jie-Mei; Zhang, Kezhong (2016) Microarray analysis of microRNA expression in bone marrow-derived progenitor cells from mice with type 2 diabetes. Genom Data 7:86-7
Dandekar, Aditya; Qiu, Yining; Kim, Hyunbae et al. (2016) Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin. J Biol Chem 291:23149-23158
Zhang, Kezhong; Wang, Guohui; Zhang, Xuebao et al. (2016) COX7AR is a Stress-inducible Mitochondrial COX Subunit that Promotes Breast Cancer Malignancy. Sci Rep 6:31742
Zheng, Ze; Kim, Hyunbae; Qiu, Yining et al. (2016) CREBH Couples Circadian Clock With Hepatic Lipid Metabolism. Diabetes 65:3369-3383
Zheng, Ze; Wang, Guohui; Li, Li et al. (2016) Transcriptional signatures of unfolded protein response implicate the limitation of animal models in pathophysiological studies. Environ Dis 1:24-30
Kim, Hyunbae; Mendez, Roberto; Chen, Xuequn et al. (2015) Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism. Mol Cell Biol 35:4121-34

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