(955.5) Inhalation Exposure to Airborne PM2.5 Induces Integrated Organelle Stress Response in the Liver

Poster Board Number: E582

Kezhong Zhang (Wayne State University), Lawrence Grossman (Wayne State University), Paul Stemmer (Wayne State University), Hyunbae Kim (Wayne State University), Nicholas Carruthers (Wayne State University)

Air pollution is a sustained problem of public health for the general population. Accumulating evidence has confirmed a significant association between exposure to fine ambient particulate matter with aerodynamic diameters lt; 2.5 μm (PM2.5) and the increase of morbidity and mortality associated with cardiovascular and metabolic diseases. Chronic inflammation and dysregulated energy metabolism have been identified as the driving force of the PM2.5-caused pathogenesis. However, a precise understanding of the molecular and cellular mechanisms by which PM2.5 induces inflammatory stress responses and impairs energy homeostasis remains elusive. Research in our laboratory has addressed the mechanistic basis underlying the pathophysiologic effects of PM2.5 exposure on liver and adipose tissues with mouse models under inhalation exposure to environmentally relevant PM2.5. Proteomics analysis with PM2.5-exposed mouse liver tissues indicated that mitochondria and endoplasmic reticulum (ER) are the most sensitive organelles in transducing signaling cascades upon PM2.5 stimulation. Further investigation revealed that inhalation exposure to PM2.5 induces an integrated ER stress and mitochondrial stress response in mouse livers. Under PM2.5 exposure, the ER and mitochondria interact and build up a platform through Mitochondria-Associated Membranes (MAMs) to augment an integrated inflammatory stress response, mediated through the primary ER stress sensor IRE1α and Toll-like receptor (TLR) 2 and 4. This integrated organelle stress response pathway promoted non-alcoholic steatohepatitis (NASH), characterized by hepatic inflammation, steatosis and fibrogenesis, hepatic glycogen depletion, and insulin resistance in PM2.5-exposed mice. Disruption of MAMs by knockdown of the MAM-residing ER chaperone Sigma-1 Receptor (Sig-1R) or mitofusin (MNF2) in Kupffer cells or hepatocytes suppressed PM2.5-induced NASH and insulin resistance in mice. Together, our studies suggested that exposure to airborne PM2.5 pollution activates an integrated ER and mitochondrial stress response in the liver, which promotes NASH, disrupts energy homeostasis, and impairs insulin signaling associated with the development of metabolic syndrome. These findings provide significant insights into the hepatic pathways underlying PM2.5-triggered liver pathology, and have important implications in the understanding, prevention, and treatment of air pollution-associated metabolic disease.

Portions of this work were supported by National Institutes of Health (NIH) grants DK090313 and DK126908, and a pilot grant from the Wayne State University CURES Center Grant NIH P30 ES020957.