Cell Metabolism
Volume 20, Issue 5, 4 November 2014, Pages 787-798
Journal home page for Cell Metabolism

Article
The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism

https://doi.org/10.1016/j.cmet.2014.09.004Get rights and content
Under a Creative Commons license
open access

Highlights

  • GWAS identifies ALOX5 to associate with plasma cholesterol and HDL-C in humans

  • Aspirin promotes reverse cholesterol transport (RCT) via Abcb11

  • Lipoxins and leukotrienes regulate expression of Abcb11

  • Lipoxin mimetics increase hepatic LDLr thereby lowering LDL-C

Summary

Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolome as conserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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Co-first author