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 März; 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 März, 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

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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.

Omega-6 polyunsaturated fatty acids, including arachidonic acid (AA), have beneficial cardiovascular effects. Demetz et al. show that Alox5, a key enzyme of the AA pathway, regulates cholesterol in humans. Modulation of the AA pathways genetically or pharmacologically, with aspirin or bioactive AA-mimetics influences cholesterol metabolism including reverse cholesterol transport.

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 - 2014 Nov 4
Externally published	Yes

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2014.09.004

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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

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, März, 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

@article{f7c554a7a845401fa470a833e6fb5523,

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.Omega-6 polyunsaturated fatty acids, including arachidonic acid (AA), have beneficial cardiovascular effects. Demetz et al. show that Alox5, a key enzyme of the AA pathway, regulates cholesterol in humans. Modulation of the AA pathways genetically or pharmacologically, with aspirin or bioactive AA-mimetics influences cholesterol metabolism including reverse cholesterol transport.",

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 M{\"a}rz 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",

note = "Funding Information: This work was supported by the Austrian Research Fund, FWF (P-19664, TRP-188 to G.W.; F3517-B20 to M.T.; and P23853-B13 to I. Tancevski); by the Medizinische Forschungsfoerderung Innsbruck (MFI Number 4316 to I. Tancevski); by the Tiroler Wissenschaftsfond (TWF Number UNI-0404/965 to I. Tancevski); by the University of Milan (Piano Sviluppo B-2014 to G.D.N.); and by the Telethon Foundation (GGP13002 to G.D.N.). Publisher Copyright: {\textcopyright} 2014 The Authors.",

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",

}

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 - März, 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

N1 - Funding Information: This work was supported by the Austrian Research Fund, FWF (P-19664, TRP-188 to G.W.; F3517-B20 to M.T.; and P23853-B13 to I. Tancevski); by the Medizinische Forschungsfoerderung Innsbruck (MFI Number 4316 to I. Tancevski); by the Tiroler Wissenschaftsfond (TWF Number UNI-0404/965 to I. Tancevski); by the University of Milan (Piano Sviluppo B-2014 to G.D.N.); and by the Telethon Foundation (GGP13002 to G.D.N.). Publisher Copyright: © 2014 The Authors.

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.Omega-6 polyunsaturated fatty acids, including arachidonic acid (AA), have beneficial cardiovascular effects. Demetz et al. show that Alox5, a key enzyme of the AA pathway, regulates cholesterol in humans. Modulation of the AA pathways genetically or pharmacologically, with aspirin or bioactive AA-mimetics influences cholesterol metabolism including reverse cholesterol transport.

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.Omega-6 polyunsaturated fatty acids, including arachidonic acid (AA), have beneficial cardiovascular effects. Demetz et al. show that Alox5, a key enzyme of the AA pathway, regulates cholesterol in humans. Modulation of the AA pathways genetically or pharmacologically, with aspirin or bioactive AA-mimetics influences cholesterol metabolism including reverse cholesterol transport.

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DO - 10.1016/j.cmet.2014.09.004

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SN - 1550-4131

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EP - 798

JO - Cell Metabolism

JF - Cell Metabolism

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ER -

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

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