title: Kupffer cell activation by ambient air particulate matter exposure may exacerbate non-alcoholic fatty liver disease.
abstract: Owing to increased obesity, non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver disease in the United States. NAFLD is considered a component of metabolic syndrome, a cluster of disorders that also includes diabetes mellitus, dyslipidemia, arteriosclerosis, and hypertension. Exposure to ambient air particulate matter with aerodynamic diameters < 2.5 microm (PM(2.5)) is a risk factor for arteriosclerosis and lung disease, but its effect on NAFLD is unknown. PM(2.5) induces pulmonary dysfunction via Toll-like receptor (TLR) activation on alveolar macrophages. TLR activation of Kupffer cells, resident hepatic macrophages, and subsequent pro-inflammatory cytokine production have been shown to play a key role in NAFLD progression. We hypothesized that PM(2.5) exposure is a significant risk factor for the progression of NAFLD. Thus, following exposure of male C57BL/6 mice fed high fat chow (HFC) to concentrated air particulate matter (CAPs) or filtered air for 6 weeks, progression of NAFLD was evaluated by standardized histological assessment of hepatic inflammation and fibrosis. In mice fed HFC, the hepatic inflammatory grade (3.00 +/- 0.00 vs. 1.50 +/- 0.71, P < 0.001) and fibrosis stage (1.00 +/- 0.00 vs. 0.60 +/- 0.52, P = 0.023) were both significantly higher in mice exposed to CAPs versus filtered air, respectively. Increased numbers of Kupffer cells contained PM in CAPs-exposed mice scores of (2.00 +/- 0.94 vs. 0.20 +/- 0.42, respectively, P < 0.001). PM exposure increased IL-6 secretion up to seven-fold in a dose-dependent manner by isolated wild-type but not TLR4(-/-) Kupffer cells (P < 0.050). In conclusion, ambient PM(2.5) exposure may be a significant risk factor for NAFLD progression.
authors.affiliation: Department of Medicine, The Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Tan
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Fiel
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Guo
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gordon
authors.forename: Lung-Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Odin
authors.forename: Jorge
authors.initials: J
authors.lastname: Allina
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D019570:Inhalation Exposure; D007728:Kupffer Cells / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052638:Particulate Matter / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter