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Cell Metab. 2014 Nov 4;20(5):787-798. doi: 10.1016/j.cmet.2014.09.004.

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

Author information

1
Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
2
Department of Internal Medicine, Angiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
3
Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
4
Department of Ophthalmology and Optometry, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
5
Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
6
Department of Pharmacology, Capital Medical University, Number 10 Xitoutiao, You An Men, 100069 Beijing, China.
7
Department of Pediatrics II, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
8
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
9
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.
10
Department of Internal Medicine, Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
11
Center for the Study of Atherosclerosis, Bassini Hospital, via Gorki 50, 20092 Cinisello Balsamo Milan, Italy.
12
Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
13
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.
14
Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
15
Department of Medicine and Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
16
Department of Biological Informatics and Experimental Therapeutics, Graduate School of Medicine, Akita University, 1-1 Tegata Gakuen-machi, 010-8502 Akita City, Japan.
17
Department of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo, 113-8654 Tokyo, Japan.
18
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS313, Memphis, TN 38105, USA.
19
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.
20
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
21
Center for the Study of Atherosclerosis, Bassini Hospital, via Gorki 50, 20092 Cinisello Balsamo Milan, Italy; Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy; The Blizard Institute, Centre for Diabetes, Barts and The London School of Medicine & Dentistry, Queen Mary University, 4 Newark Street, E1 2AT London, UK.
22
Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: guenter.weiss@i-med.ac.at.
23
Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: ivan.tancevski@i-med.ac.at.

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.

PMID:
25444678
PMCID:
PMC4232508
DOI:
10.1016/j.cmet.2014.09.004
[Indexed for MEDLINE]
Free PMC Article

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