The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism

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 co...

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Published in:Cell metabolism Vol. 20; no. 5; p. 787
Main Authors: Demetz, Egon, Schroll, Andrea, Auer, Kristina, Heim, Christiane, Patsch, Josef R, Eller, Philipp, Theurl, Markus, Theurl, Igor, Theurl, Milan, Seifert, Markus, Lener, Daniela, Stanzl, Ursula, Haschka, David, Asshoff, Malte, Dichtl, Stefanie, Nairz, Manfred, Huber, Eva, Stadlinger, Martin, Moschen, Alexander R, Li, Xiaorong, Pallweber, Petra, Scharnagl, Hubert, Stojakovic, Tatjana, März, Winfried, Kleber, Marcus E, Garlaschelli, Katia, Uboldi, Patrizia, Catapano, Alberico L, Stellaard, Frans, Rudling, Mats, Kuba, Keiji, Imai, Yumiko, Arita, Makoto, Schuetz, John D, Pramstaller, Peter P, Tietge, Uwe J F, Trauner, Michael, Norata, Giuseppe D, Claudel, Thierry, Hicks, Andrew A, Weiss, Guenter, Tancevski, Ivan
Format: Journal Article
Language:English
Published: United States 04.11.2014
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Arachidonate 5-Lipoxygenase - metabolism
Arachidonic Acid - metabolism
Aspirin - therapeutic use
Atherosclerosis - drug therapy
Atherosclerosis - metabolism
Bile Acids and Salts - metabolism
Cells, Cultured
Cholesterol - blood
Cholesterol - metabolism
Cholesterol, HDL - blood
Cholesterol, HDL - metabolism
Humans
Leukotrienes - metabolism
Liver - drug effects
Liver - metabolism
Metabolome
Mice
Mice, Inbred C57BL
ISSN:1932-7420, 1932-7420
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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 metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2014.09.004