Proinflammatory Adipokine Leptin Mediates Disinfection Byproduct Bromodichloromethane-Induced Early Steatohepatitic Injury in Obesity

Toxicol Appl Pharmacol. 2013 Jun 15;269(3):297-306. doi: 10.1016/j.taap.2013.02.003. Epub 2013 Feb 22.

Abstract

Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adipokines / pharmacology*
  • Animals
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Liver / chemically induced*
  • Fatty Liver / prevention & control
  • In Situ Nick-End Labeling
  • Kupffer Cells / drug effects
  • Leptin / analysis
  • Liver / chemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microscopy, Confocal
  • Obesity / complications*
  • Real-Time Polymerase Chain Reaction
  • Trihalomethanes / antagonists & inhibitors
  • Trihalomethanes / toxicity

Substances

  • Adipokines
  • Leptin
  • Trihalomethanes
  • bromodichloromethane