Archives of Toxicology

, Volume 91, Issue 4, pp 1709–1725 | Cite as

Acrolein increases macrophage atherogenicity in association with gut microbiota remodeling in atherosclerotic mice: protective role for the polyphenol-rich pomegranate juice

  • Oren RomEmail author
  • Hila Korach-Rechtman
  • Tony Hayek
  • Yael Danin-Poleg
  • Haim Bar
  • Yechezkel Kashi
  • Michael Aviram
Molecular Toxicology


The unsaturated aldehyde acrolein is pro-atherogenic, and the polyphenol-rich pomegranate juice (PJ), known for its anti-oxidative/anti-atherogenic properties, inhibits macrophage foam cell formation, the hallmark feature of early atherosclerosis. This study aimed to investigate two unexplored areas of acrolein atherogenicity: macrophage lipid metabolism and the gut microbiota composition. The protective effects of PJ against acrolein atherogenicity were also evaluated. Atherosclerotic apolipoprotein E-deficient (apoE−/−) mice that were fed acrolein (3 mg/kg/day) for 1 month showed significant increases in serum and aortic cholesterol, triglycerides, and lipid peroxides. In peritoneal macrophages isolated from the mice and in J774A.1 cultured macrophages, acrolein exposure increased intracellular oxidative stress and stimulated cholesterol and triglyceride accumulation via enhanced rates of their biosynthesis and over-expression of key regulators of cellular lipid biosynthesis: sterol regulatory element-binding proteins (SREBPs), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and diacylglycerol acyltransferase1 (DGAT1). Acrolein-fed mice demonstrated a major shift in the gut microbiota composition, including a significant phylum-level change in increased Firmicutes and decreased Bacteroidetes. At the family level, acrolein significantly increased the prevalence of Ruminococcaceae and Lachnospiraceae of which the Coprococcus genus was significantly and positively correlated with serum, aortic and macrophage lipid levels and peroxidation. The pro-atherogenic effects of acrolein on serum, aortas, macrophages, and the gut microbiota were substantially abolished by PJ. In conclusion, these findings provide novel mechanisms by which acrolein increases macrophage lipid accumulation and alters the gut microbiota composition in association with enhanced atherogenesis. Moreover, PJ was found as an effective strategy against acrolein atherogenicity.


Acrolein Gut microbiota Lipid metabolism Macrophage foam cells Oxidative stress 



This work was supported by: Technion Rappaport Institute for Research in the Medical Sciences, Bio Rap Technologies, and the Clinical Research Institute at Rambam. Special thanks to Mira Rosenblat, Nina Volkova, and Dr. Niroz Abu-Saleh for their valuable technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed.

Supplementary material

204_2016_1859_MOESM1_ESM.pdf (579 kb)
Supplementary material 1 (PDF 580 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Oren Rom
    • 1
    Email author
  • Hila Korach-Rechtman
    • 2
  • Tony Hayek
    • 1
    • 3
  • Yael Danin-Poleg
    • 2
  • Haim Bar
    • 4
  • Yechezkel Kashi
    • 2
  • Michael Aviram
    • 1
  1. 1.The Lipid Research Laboratory, Rappaport Faculty of MedicineTechnion—Israel Institute of TechnologyHaifaIsrael
  2. 2.Laboratory of Applied Genomics, Faculty of Biotechnology and Food EngineeringTechnion—Israel Institute of TechnologyHaifaIsrael
  3. 3.Department of Internal Medicine ERambam Health Care CampusHaifaIsrael
  4. 4.Department of StatisticsUniversity of ConnecticutStorrsUSA

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