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

研究成果: Article

45 引用 (Scopus)

抜粋

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.

元の言語English
ページ(範囲)787-798
ページ数12
ジャーナルCell Metabolism
20
発行部数5
DOI
出版物ステータスPublished - 2014 11 4

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

これを引用

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