Airborne Particulate Matter, Endoplasmic Reticulum Stress and Hepatic Lipid Dysre

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DESCRIPTION (provided by applicant): 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.