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

被引：102

作者：

Demetz, Egon ^{[1
]}

Schroll, Andrea ^{[1
]}

Auer, Kristina ^{[1
]}

Heim, Christiane ^{[1
]}

Patsch, Josef R. ^{[1
]}

Eller, Philipp ^{[2
]}

Theurl, Markus ^{[3
]}

Theurl, Igor ^{[1
]}

Theurl, Milan ^{[4
]}

Seifert, Markus ^{[1
]}

Lener, Daniela ^{[3
]}

Stanzl, Ursula ^{[3
]}

Haschka, David ^{[1
]}

Asshoff, Malte ^{[1
]}

Dichtl, Stefanie ^{[1
]}

Nairz, Manfred ^{[1
]}

Huber, Eva ^{[1
]}

Stadlinger, Martin ^{[1
]}

Moschen, Alexander R. ^{[5
]}

Li, Xiaorong ^{[6
]}

Pallweber, Petra ^{[7
]}

Scharnagl, Hubert ^{[8
]}

Stojakovic, Tatjana ^{[8
]}

Maerz, Winfried ^{[8
,9
,10
]}

Kleber, Marcus E. ^{[9
]}

Garlaschelli, Katia ^{[11
]}

Uboldi, Patrizia ^{[12
]}

Catapano, Alberico L. ^{[12
,13
]}

Stellaard, Frans ^{[14
]}

Rudling, Mats ^{[15
,16
]}

Kuba, Keiji ^{[17
]}

Imai, Yumiko ^{[17
]}

Arita, Makoto ^{[18
]}

Schuetz, John D. ^{[19
]}

Pramstaller, Peter P. ^{[20
,21
]}

Tietge, Uwe J. F. ^{[14
]}

Trauner, Michael ^{[22
]}

Norata, Giuseppe D. ^{[11
,12
,23
]}

Claudel, Thierry ^{[22
]}

Hicks, Andrew A. ^{[20
,21
]}

Weiss, Guenter ^{[1
]}

Tancevski, Ivan ^{[1
]}

机构：

[1] Med Univ Innsbruck, Dept Internal Med 6, A-6020 Innsbruck, Austria

[2] Med Univ Graz, Dept Internal Med, A-8036 Graz, Austria

[3] Med Univ Innsbruck, Dept Internal Med 3, A-6020 Innsbruck, Austria

[4] Med Univ Innsbruck, Dept Ophthalmol & Optometry, A-6020 Innsbruck, Austria

[5] Med Univ Innsbruck, Dept Internal Med 1, A-6020 Innsbruck, Austria

[6] Capital Med Univ, Dept Pharmacol, Beijing 100069, Peoples R China

[7] Med Univ Innsbruck, Dept Pediat 2, A-6020 Innsbruck, Austria

[8] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria

[9] Heidelberg Univ, Mannheim Med Fac, Dept Internal Med, Med Clin 5, D-68167 Mannheim, Germany

[10] Synlab Acad, D-68163 Mannheim, Germany

[11] Bassini Hosp, Ctr Study Atherosclerosis, I-20092 Cinisello Balsamo Milan, Italy

[12] Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy

[13] IRCCS Multimed, I-20099 Sesto San Giovanni Milan, Italy

[14] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, NL-9700 RB Groningen, Netherlands

[15] Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Med, S-14186 Stockholm, Sweden

[16] Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Biosci & Nutr, S-14186 Stockholm, Sweden

[17] Akita Univ, Grad Sch Med, Dept Biol Informat & Expt Therapeut, Akita 0108502, Japan

[18] Univ Tokyo, Dept Hlth Chem, Bunkyo Ku, Tokyo 1138654, Japan

[19] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[20] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy

[21] Med Univ Lubeck, Affiliated Inst, D-23562 Lubeck, Germany

[22] Med Univ Vienna, Div Gastroenterol & Hepatol, Dept Internal Med 3, Hans Popper Lab Mol Hepatol, A-1090 Vienna, Austria

[23] Queen Mary Univ, Barts & London Sch Med & Dent, Ctr Diabet, Blizard Inst, London E1 2AT, England

来源：

CELL METABOLISM | 2014年 / 20卷 / 05期

基金：

奥地利科学基金会;

关键词：

SALT EXPORT PUMP; MYOCARDIAL-INFARCTION; ACUTE-INFLAMMATION; LIPID MEDIATORS; FATTY-ACIDS; ASPIRIN; GENE; 5-LIPOXYGENASE; TRANSPORT; OVEREXPRESSION;

D O I：

10.1016/j.cmet.2014.09.004

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：787 / 798

页数：12

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