title: The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism.
abstract: 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.
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.lastname: Demetz
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Kristina
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Christiane
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine, Angiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
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authors.affiliation: Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Igor
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authors.affiliation: Department of Ophthalmology and Optometry, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Milan
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Markus
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authors.affiliation: Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Ursula
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Department of Pharmacology, Capital Medical University, Number 10 Xitoutiao, You An Men, 100069 Beijing, China.
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authors.affiliation: Department of Pediatrics II, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
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authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
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authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Department of Internal Medicine, Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Synlab Academy, Harrlachweg 1, 68163 Mannheim, Germany.
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authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Patrizia
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authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy; IRCCS Multimedica, via Milanese 300, 20099 Sesto San Giovanni Milan, Italy.
authors.forename: Alberico L
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authors.affiliation: Department of Biological Informatics and Experimental Therapeutics, Graduate School of Medicine, Akita University, 1-1 Tegata Gakuen-machi, 010-8502 Akita City, Japan.
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authors.affiliation: Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Drususallee 1, 39100 Bolzano, Italy-Affiliated Institute of the University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany.
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authors.forename: Andrew A
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authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: guenter.weiss@i-med.ac.at.
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mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D001241:Aspirin / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D015289:Leukotrienes; D016718:Arachidonic Acid; D002784:Cholesterol; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D001241:Aspirin