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

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

doi:10.1016/j.cmet.2014.09.004

Abstract

SummaryCholesterol 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.

Highlights

Atherosclerosis is still the leading cause of death in industrialized countries, and novel therapies to lower low-density lipoproteinCell Metabolism 20, 787–798, November 4, 2014 a2014 The Authors 787Arachidonic Acid Metabolome and Cholesterol cholesterol (LDL-C) are urgently needed
By combining data from a genome-wide association studies (GWASs) screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the arachidonic acid (AA) metabolome as an important regulator of cholesterol homeostasis
It is well known that dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) reduces the risk of cardiovascular disease (CAD) (Harris et al, 2009; Katan, 2009), which is in part attributable to the observation that increased AA plasma levels are associated with beneficial changes in LDL-C and high-density lipoprotein (HDL)-C

Summary

Introduction

Atherosclerosis is still the leading cause of death in industrialized countries, and novel therapies to lower low-density lipoproteinCell Metabolism 20, 787–798, November 4, 2014 a2014 The Authors 787Arachidonic Acid Metabolome and Cholesterol cholesterol (LDL-C) are urgently needed. Whereas PGs and TXs are formed by cyclooxygenases I and II (COX I/II), LTs are generated through the action of arachidonate 5-lipoxygenase (ALOX5), and LXs—an acronym of lipoxygenase interaction product—by the sequential cell-cell interaction of different lipoxygenases (McMahon and Godson, 2004; Serhan, 2007): LTA4, the intermediate of LT synthesis, is produced in neutrophils via ALOX5 and can be taken up by platelets and converted into LXs via ALOX12. Aspirin acetylates COX II, changing its activity to a lipoxygenase This generates 15R-HETE, which is converted into 15-epi-lipoxins via ALOX5 (McMahon and Godson, 2004; Serhan, 2007)

Results

Discussion

Conclusion