Exposure to a Northern Contaminant Mixture (NCM) Alters Hepatic Energy and Lipid Metabolism Exacerbating Hepatic Steatosis in Obese JCR Rats

PLoS One. 2014 Sep 15;9(9):e106832. doi: 10.1371/journal.pone.0106832. eCollection 2014.

Abstract

Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure to ethanol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cholesterol / metabolism
  • Environmental Exposure
  • Environmental Pollutants / adverse effects*
  • Ethanol / toxicity
  • Fatty Liver / chemically induced*
  • Homeostasis / drug effects
  • Humans
  • Inuits
  • Lipid Metabolism / drug effects*
  • Liver / drug effects
  • Liver / metabolism
  • Rats, Inbred Strains

Substances

  • Environmental Pollutants
  • Ethanol
  • Adenosine Triphosphate
  • Cholesterol

Grant support

This work was supported by a research grant (to XJ) from Health Canada and the Northern Contaminants Program as part of a Government of Canada initiative to address potential health risks that may be associated with human exposure to elevated levels of contaminants in the traditional diets of northern Aboriginal peoples, and a discovery grant (to WGW) from the Natural Sciences and Engineering Research Council of Canada. The funders had no role in study design, data collection and analysis, preparation of the manuscript or the decision to publish.