title: Environmental toxin-linked nonalcoholic steatohepatitis and hepatic metabolic reprogramming in obese mice.
abstract: Obesity is associated with strong risks of development of chronic inflammatory liver disease and metabolic syndrome following a second hit. This study tests the hypothesis that free radical metabolism of low chronic exposure to bromodichloromethane (BDCM), a disinfection byproduct of drinking water, causes nonalcoholic steatohepatitis (NASH), mediated by cytochrome P450 isoform CYP2E1 and adipokine leptin. Using diet-induced obese mice (DIO), mice deficient in CYP2E1, and mice with spontaneous knockout of the leptin gene, we show that BDCM caused increased lipid peroxidation and increased tyrosine nitration in DIO mice, events dependent on reductive metabolism by CYP2E1. DIO mice, exposed to BDCM, exhibited increased hepatic leptin levels and higher levels of proinflammatory gene expression and Kupffer cell activation. Obese mice exposed to BDCM also showed profound hepatic necrosis, Mallory body formation, collagen deposition, and higher alpha smooth muscle actin expression, events that are hallmarks of NASH. The absence of CYP2E1 gene in mice that were fed with a high-fat diet did not show NASH symptoms and were also protected from hepatic metabolic alterations in Glut-1, Glut-4, phosphofructokinase and phosphoenolpyruvate carboxykinase gene expressions (involved in carbohydrate metabolism), and UCP-1, PGC-1α, SREBP-1c, and PPAR-γ genes (involved in hepatic fat metabolism). Mice lacking the leptin gene were significantly protected from both NASH and metabolic alterations following BDCM exposure, suggesting that higher levels of leptin induction by BDCM in the liver contribute to the development of NASH and metabolic alterations in obesity. These results provide novel insights into BDCM-induced NASH and hepatic metabolic reprogramming and show the regulation of obesity-linked susceptibility to NASH by environmental factors, CYP2E1, and leptin.
authors: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208, USA.
authors: Ratanesh Kumar
authors: RK
authors: Seth
authors: Ashutosh
authors: A
authors: Kumar
authors: Suvarthi
authors: S
authors: Das
authors: Maria B
authors: MB
authors: Kadiiska
authors: Gregory
authors: G
authors: Michelotti
authors: Anna Mae
authors: AM
authors: Diehl
authors: Saurabh
authors: S
authors: Chatterjee
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005223:Fats / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D004785:Environmental Pollutants; D005223:Fats; D020738:Leptin; D019392:Cytochrome P-450 CYP2E1; D005947:Glucose
keywords: Glut-1; PPAR-γ; SREBP-1c; bromodichloromethane; fibrosis; gluconeogenesis; glycolysis; hepatocyte; lipid peroxidation; ob/ob mice.; tumor necrosis factor
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