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

Egon Demetz; Andrea Schroll; Kristina Auer; Christiane Heim; Josef R. Patsch; Philipp Eller; Markus Theurl; Igor Theurl; Milan Theurl; Markus Seifert; Daniela Lener; Ursula Stanzl; David Haschka; Malte Asshoff; Stefanie Dichtl; Manfred Nairz; Eva Huber; Martin Stadlinger; Alexander R. Moschen; Xiaorong Li; Petra Pallweber; Hubert Scharnagl; Tatjana Stojakovic; Winfried Maerz; Marcus E. Kleber; Katia Garlaschelli; Patrizia Uboldi; Alberico L. Catapano; Frans Stellaard; Mats Rudling; Keiji Kuba; Yumiko Imai; Makoto Arita; John D. Schuetz; Peter P. Pramstaller; Uwe J. F. Tietge; Michael Trauner; Giuseppe D. Norata; Thierry Claudel; Andrew A. Hicks; Guenter Weiss; Ivan Tancevski

doi:10.1016/j.cmet.2014.09.004

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

Egon Demetz, Andrea Schroll, Kristina Auer, Christiane Heim, Josef R. Patsch, Philipp Eller, Markus Theurl, Igor Theurl, Milan Theurl, Markus Seifert, Daniela Lener, Ursula Stanzl, David Haschka, Malte Asshoff, Stefanie Dichtl, Manfred Nairz, Eva Huber, Martin Stadlinger, Alexander R. Moschen, Xiaorong LiPetra Pallweber, Hubert Scharnagl, Tatjana Stojakovic, Winfried Maerz, Marcus E. Kleber, Katia Garlaschelli, Patrizia Uboldi, Alberico L. Catapano, Frans Stellaard, Mats Rudling, Keiji Kuba, Yumiko Imai, Makoto Arita, John D. Schuetz, Peter P. Pramstaller, Uwe J. F. Tietge, Michael Trauner, Giuseppe D. Norata, Thierry Claudel, Andrew A. Hicks, Guenter Weiss^*, Ivan Tancevski

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 metabolome as conserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.

Original language	English
Pages (from-to)	787-798
Number of pages	12
Journal	Cell Metabolism
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2014.09.004
Publication status	Published - 4-Nov-2014

Keywords

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

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Demetz, E., Schroll, A., Auer, K., Heim, C., Patsch, J. R., Eller, P., Theurl, M., Theurl, I., Theurl, M., Seifert, M., Lener, D., Stanzl, U., Haschka, D., Asshoff, M., Dichtl, S., Nairz, M., Huber, E., Stadlinger, M., Moschen, A. R., ... Tancevski, I. (2014). The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism. Cell Metabolism, 20(5), 787-798. https://doi.org/10.1016/j.cmet.2014.09.004

@article{23fad33e227345059a397c7f53881440,

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 metabolome as conserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.",

keywords = "SALT EXPORT PUMP, MYOCARDIAL-INFARCTION, ACUTE-INFLAMMATION, LIPID MEDIATORS, FATTY-ACIDS, ATHEROSCLEROSIS, TRANSPORT, ASPIRIN, GENE, 5-LIPOXYGENASE",

author = "Egon Demetz and Andrea Schroll and Kristina Auer and Christiane Heim and Patsch, {Josef R.} and Philipp Eller and Markus Theurl and Igor Theurl and Milan Theurl and Markus Seifert and Daniela Lener and Ursula Stanzl and David Haschka and Malte Asshoff and Stefanie Dichtl and Manfred Nairz and Eva Huber and Martin Stadlinger and Moschen, {Alexander R.} and Xiaorong Li and Petra Pallweber and Hubert Scharnagl and Tatjana Stojakovic and Winfried Maerz and Kleber, {Marcus E.} and Katia Garlaschelli and Patrizia Uboldi and Catapano, {Alberico L.} and Frans Stellaard and Mats Rudling and Keiji Kuba and Yumiko Imai and Makoto Arita and Schuetz, {John D.} and Pramstaller, {Peter P.} and Tietge, {Uwe J. F.} and Michael Trauner and Norata, {Giuseppe D.} and Thierry Claudel and Hicks, {Andrew A.} and Guenter Weiss and Ivan Tancevski",

year = "2014",

month = nov,

day = "4",

doi = "10.1016/j.cmet.2014.09.004",

language = "English",

volume = "20",

pages = "787--798",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "5",

}

Demetz, E, Schroll, A, Auer, K, Heim, C, Patsch, JR, Eller, P, Theurl, M, Theurl, I, Theurl, M, Seifert, M, Lener, D, Stanzl, U, Haschka, D, Asshoff, M, Dichtl, S, Nairz, M, Huber, E, Stadlinger, M, Moschen, AR, Li, X, Pallweber, P, Scharnagl, H, Stojakovic, T, Maerz, W, Kleber, ME, Garlaschelli, K, Uboldi, P, Catapano, AL, Stellaard, F, Rudling, M, Kuba, K, Imai, Y, Arita, M, Schuetz, JD, Pramstaller, PP, Tietge, UJF, Trauner, M, Norata, GD, Claudel, T, Hicks, AA, Weiss, G & Tancevski, I 2014, 'The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism', Cell Metabolism, vol. 20, no. 5, pp. 787-798. https://doi.org/10.1016/j.cmet.2014.09.004

TY - JOUR

T1 - The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism

AU - Demetz, Egon

AU - Schroll, Andrea

AU - Auer, Kristina

AU - Heim, Christiane

AU - Patsch, Josef R.

AU - Eller, Philipp

AU - Theurl, Markus

AU - Theurl, Igor

AU - Theurl, Milan

AU - Seifert, Markus

AU - Lener, Daniela

AU - Stanzl, Ursula

AU - Haschka, David

AU - Asshoff, Malte

AU - Dichtl, Stefanie

AU - Nairz, Manfred

AU - Huber, Eva

AU - Stadlinger, Martin

AU - Moschen, Alexander R.

AU - Li, Xiaorong

AU - Pallweber, Petra

AU - Scharnagl, Hubert

AU - Stojakovic, Tatjana

AU - Maerz, Winfried

AU - Kleber, Marcus E.

AU - Garlaschelli, Katia

AU - Uboldi, Patrizia

AU - Catapano, Alberico L.

AU - Stellaard, Frans

AU - Rudling, Mats

AU - Kuba, Keiji

AU - Imai, Yumiko

AU - Arita, Makoto

AU - Schuetz, John D.

AU - Pramstaller, Peter P.

AU - Tietge, Uwe J. F.

AU - Trauner, Michael

AU - Norata, Giuseppe D.

AU - Claudel, Thierry

AU - Hicks, Andrew A.

AU - Weiss, Guenter

AU - Tancevski, Ivan

PY - 2014/11/4

Y1 - 2014/11/4

N2 - 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.

AB - 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.

KW - SALT EXPORT PUMP

KW - MYOCARDIAL-INFARCTION

KW - ACUTE-INFLAMMATION

KW - LIPID MEDIATORS

KW - FATTY-ACIDS

KW - ATHEROSCLEROSIS

KW - TRANSPORT

KW - ASPIRIN

KW - GENE

KW - 5-LIPOXYGENASE

U2 - 10.1016/j.cmet.2014.09.004

DO - 10.1016/j.cmet.2014.09.004

M3 - Article

SN - 1550-4131

VL - 20

SP - 787

EP - 798

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

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

Abstract

Keywords

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