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

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 co...

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Main Authors:	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
Format:	Online
Language:	English
Published:	Cell Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232508/

id	pubmed-4232508
recordtype	oai_dc
spelling	pubmed-42325082014-11-18 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 Article 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. Cell Press 2014-11-04 /pmc/articles/PMC4232508/ /pubmed/25444678 http://dx.doi.org/10.1016/j.cmet.2014.09.004 Text en © 2014 The Authors
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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
spellingShingle	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
author_facet	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
author_sort	Demetz, Egon
title	The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism
title_short	The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism
title_full	The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism
title_fullStr	The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism
title_full_unstemmed	The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism
title_sort	arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism
description	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.
publisher	Cell Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232508/
_version_	1613156806464372736

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

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