Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model

Background & Aims: Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters <2.5 mu m (PM2.5) to the development of metabolic diseases. In this study, we investigated the effect of PM2.5 exposure on liver pathogenesis and the mechanism by which ambient PM2.5 modulates hepatic pathways and glucose homeostasis. Methods: Using "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1", we performed whole-body exposure of mice to concentrated ambient PM2.5 for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM2.5 exposure promotes liver pathogenesis. Results: Mice exposed to PM2.5 for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM2.5 exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM2.5 led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-kappa B), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM2.5 exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)gamma and PPAR alpha in the liver. Conclusions: Our study suggests that PM2.5 exposure represents a significant "hit" that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.