Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

Lisanne C. Anders, Heegook Yeo, Brenna R. Kaelin, Anna L. Lang, Adrienne M. Bushau, Amanda N. Douglas, Matt Cave, Gavin E. Arteel, Craig J. McClain, Juliane I. Beier

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH.

Original languageEnglish (US)
Pages (from-to)34-41
Number of pages8
JournalToxicology and Applied Pharmacology
Volume311
DOIs
StatePublished - Nov 15 2016
Externally publishedYes

Keywords

  • Hepatotoxicity
  • Plastic
  • PVC
  • Saturated fat
  • TASH
  • Unsaturated fat

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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