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

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 UJ, Trauner M, Norata GD, Claudel T, Hicks AA, Weiss G, Tancevski I - Cell Metab. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria

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 metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.

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Treatment with Lipoxin Mimetics Lowers Plasma LDL-C(A) C57BL/6 mice were daily injected i.v. with vehicle (control), 10 ng 8,9-acetylenic-LXB4, or 10 ng 5-(R/S)-methyl-LXB4 for 4 days (data presented are representative of three independent experiments).(B) Plasma total cholesterol measurement in control and 8,9-acetylenic-LXB4- and 5-(R/S)-methyl-LXB4-treated mice (n = 3).(C) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 3; bars represent densitometric quantification normalized to albumin). All bars show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
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fig7: Treatment with Lipoxin Mimetics Lowers Plasma LDL-C(A) C57BL/6 mice were daily injected i.v. with vehicle (control), 10 ng 8,9-acetylenic-LXB4, or 10 ng 5-(R/S)-methyl-LXB4 for 4 days (data presented are representative of three independent experiments).(B) Plasma total cholesterol measurement in control and 8,9-acetylenic-LXB4- and 5-(R/S)-methyl-LXB4-treated mice (n = 3).(C) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 3; bars represent densitometric quantification normalized to albumin). All bars show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.

Mentions: Finally, in an approach to translate our combined findings from GWAS analysis in humans, mediator lipidomics and functional studies in mice into the identification of novel compounds which beneficially influence plasma cholesterol levels and thus putatively the course of CAD, we reasoned to study the impact of systemic treatment with LXB4 on cholesterol metabolism in mice (Figure 7A). Because LXB4 is unstable and rapidly inactivated within the circulation, we performed daily i.v. injections into mice with synthetic stable analogs of LXB4 including 5-(R/S)-methyl-LXB4 and 8,9-acetylenic-LXB4, the latter being a log order of magnitude less potent than LXB4 (Maddox et al., 1998). After 4 days of treatment, 8,9-acetylenic-LXB4 caused a nonsignificant ∼15% decrease in plasma total cholesterol, whereas 5-(R/S)-methyl-LXB4 significantly reduced plasma cholesterol levels by ∼30% (Figure 7B). FPLC analysis showed a decrease in LDL-C in 5-(R/S)-methyl-LXB4-treated mice, whereas HDL-C remained unchanged (Figure S5). Accordingly, treatment with 5-(R/S)-methyl-LXB4 was associated with an ∼3-fold increase in the protein expression of hepatic LDLr and a moderate increase in hepatic protein levels of SR-BI (Figure 7C). Abcb11 protein expression was decreased in animals treated with LX mimetics compared to controls.


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

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 UJ, Trauner M, Norata GD, Claudel T, Hicks AA, Weiss G, Tancevski I - Cell Metab. (2014)

Treatment with Lipoxin Mimetics Lowers Plasma LDL-C(A) C57BL/6 mice were daily injected i.v. with vehicle (control), 10 ng 8,9-acetylenic-LXB4, or 10 ng 5-(R/S)-methyl-LXB4 for 4 days (data presented are representative of three independent experiments).(B) Plasma total cholesterol measurement in control and 8,9-acetylenic-LXB4- and 5-(R/S)-methyl-LXB4-treated mice (n = 3).(C) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 3; bars represent densitometric quantification normalized to albumin). All bars show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
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fig7: Treatment with Lipoxin Mimetics Lowers Plasma LDL-C(A) C57BL/6 mice were daily injected i.v. with vehicle (control), 10 ng 8,9-acetylenic-LXB4, or 10 ng 5-(R/S)-methyl-LXB4 for 4 days (data presented are representative of three independent experiments).(B) Plasma total cholesterol measurement in control and 8,9-acetylenic-LXB4- and 5-(R/S)-methyl-LXB4-treated mice (n = 3).(C) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 3; bars represent densitometric quantification normalized to albumin). All bars show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
Mentions: Finally, in an approach to translate our combined findings from GWAS analysis in humans, mediator lipidomics and functional studies in mice into the identification of novel compounds which beneficially influence plasma cholesterol levels and thus putatively the course of CAD, we reasoned to study the impact of systemic treatment with LXB4 on cholesterol metabolism in mice (Figure 7A). Because LXB4 is unstable and rapidly inactivated within the circulation, we performed daily i.v. injections into mice with synthetic stable analogs of LXB4 including 5-(R/S)-methyl-LXB4 and 8,9-acetylenic-LXB4, the latter being a log order of magnitude less potent than LXB4 (Maddox et al., 1998). After 4 days of treatment, 8,9-acetylenic-LXB4 caused a nonsignificant ∼15% decrease in plasma total cholesterol, whereas 5-(R/S)-methyl-LXB4 significantly reduced plasma cholesterol levels by ∼30% (Figure 7B). FPLC analysis showed a decrease in LDL-C in 5-(R/S)-methyl-LXB4-treated mice, whereas HDL-C remained unchanged (Figure S5). Accordingly, treatment with 5-(R/S)-methyl-LXB4 was associated with an ∼3-fold increase in the protein expression of hepatic LDLr and a moderate increase in hepatic protein levels of SR-BI (Figure 7C). Abcb11 protein expression was decreased in animals treated with LX mimetics compared to controls.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria

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 metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.

Show MeSH
Related in: MedlinePlus