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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 languageEnglish
Pages (from-to)787-798
Number of pages12
JournalCell Metabolism
Volume20
Issue number5
DOIs
Publication statusPublished - 2014 Nov 4
Externally publishedYes

Fingerprint

Metabolome
Arachidonic Acid
Cholesterol
Omega-6 Fatty Acids
Lipoxins
Unsaturated Fatty Acids
Aspirin
Cardiovascular Diseases
Leukotrienes
Validation Studies
Genome-Wide Association Study
Liver
Dietary Supplements
Bile Acids and Salts
Homeostasis
Pharmacology

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology
  • Medicine(all)

Cite this

Demetz, E., Schroll, A., Auer, K., Heim, C., Patsch, J. R., Eller, P., ... 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

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

In: Cell Metabolism, Vol. 20, No. 5, 04.11.2014, p. 787-798.

Research output: Contribution to journalArticle

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
Demetz, Egon ; Schroll, Andrea ; Auer, Kristina ; Heim, Christiane ; Patsch, Josef R. ; Eller, Philipp ; Theurl, Markus ; Theurl, Igor ; Theurl, Milan ; Seifert, Markus ; Lener, Daniela ; Stanzl, Ursula ; Haschka, David ; Asshoff, Malte ; Dichtl, Stefanie ; Nairz, Manfred ; Huber, Eva ; Stadlinger, Martin ; Moschen, Alexander R. ; Li, Xiaorong ; Pallweber, Petra ; Scharnagl, Hubert ; Stojakovic, Tatjana ; März, Winfried ; Kleber, Marcus E. ; Garlaschelli, Katia ; Uboldi, Patrizia ; Catapano, Alberico L. ; Stellaard, Frans ; Rudling, Mats ; Kuba, Keiji ; Imai, Yumiko ; Arita, Makoto ; Schuetz, John D. ; Pramstaller, Peter P. ; Tietge, Uwe J F ; Trauner, Michael ; Norata, Giuseppe D. ; Claudel, Thierry ; Hicks, Andrew A. ; Weiss, Guenter ; Tancevski, Ivan. / The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism. In: Cell Metabolism. 2014 ; Vol. 20, No. 5. pp. 787-798.
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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.",
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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

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