Paradoxical Protective Effect of Perfluorooctanesulfonic Acid Against High-Fat Diet-Induced Hepatic Steatosis in Mice

Int J Toxicol. Sep/Oct 2018;37(5):383-392. doi: 10.1177/1091581818790934. Epub 2018 Aug 22.


Perfluorooctanesulfonic acid (PFOS) is a persistent organic pollutant with worldwide bioaccumulation due to a very long half-life. Perfluorooctanesulfonic acid exposure results in significant hepatic effects including steatosis, proliferation, hepatomegaly, and in rodents, carcinogenesis. The objective of this study was to determine whether PFOS exposure exacerbates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis pathogenesis. Eight-week-old male C57BL/6 J mice (n = 5 per group) were fed ad libitum normal chow diet (ND) alone, 60% high-fat diet (HFD) alone, ND + PFOS, and HFD + PFOS (0.0001% w/w (1 mg/kg) of PFOS) for 6 weeks. Both HFD alone and the ND + PFOS treatment induced significant adiposity and hepatomegaly, but the HFD + PFOS treatment showed a marked protection. Oil Red O staining and quantitative analysis of hepatic lipid content revealed increased hepatic steatosis in ND + PFOS and in HFD alone fed mice, which was prevented in HFD + PFOS treatment. Further studies revealed that ND + PFOS treatment significantly affected expression of lipid trafficking genes to favor steatosis, but these changes were absent in HFD + PFOS group. Specifically, expression of CD36, the major lipid importer in the cells, and peroxisome proliferator-activated receptor gamma (PPARγ), its major regulator, were induced in HFD + no treatment (NT) and ND + PFOS-fed mice but remained unchanged in HFD + PFOS mice. In conclusion, these data indicate that coadministration of PFOS with HFD mitigates steatosis and hepatomegaly induced by HFD and that by PFOS fed in ND diet via regulation of cellular lipid import machinery. These findings suggest dietary lipid content be considered when performing risk management of PFOS in humans and the elucidation of PFOS-induced hepatotoxicity.

Keywords: NFALD; nonalcoholic steatohepatitis; perfluorinated alkyl acids; steatosis.

Publication types

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

MeSH terms

  • Adiposity / drug effects
  • Alkanesulfonic Acids / administration & dosage*
  • Animals
  • Cell Proliferation / drug effects
  • Diet, High-Fat*
  • Fluorocarbons / administration & dosage*
  • Gene Expression / drug effects
  • Hepatocytes / drug effects
  • Hepatomegaly / chemically induced
  • Male
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / prevention & control*
  • Weight Gain / drug effects


  • Alkanesulfonic Acids
  • Fluorocarbons
  • perfluorooctane sulfonic acid