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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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The Role of Alox5 in Abcb11 Regulation and Cholesterol Homeostasis(A) To selectively study the Alox5 pathway, studies in Alox5+/+ and Alox5−/− mice were performed.(B) FPLC analysis of plasma pooled from Alox5+/+ and Alox5−/− mice (n = 5).(C) Plasma [3H]-cholesterol levels at indicated time points and (D) fecal [3H]-sterol levels (0–48 hr) from a macrophage-to-feces RCT study performed in Alox5+/+ and Alox5−/− mice (n = 3).(E) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 4; bars represent densitometric quantification normalized to actin). Graphs show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.(F) Mediator lipidomics in livers of Alox5+/+ and Alox5−/− mice (n = 3). Graphs show mean ± SEM.
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fig5: The Role of Alox5 in Abcb11 Regulation and Cholesterol Homeostasis(A) To selectively study the Alox5 pathway, studies in Alox5+/+ and Alox5−/− mice were performed.(B) FPLC analysis of plasma pooled from Alox5+/+ and Alox5−/− mice (n = 5).(C) Plasma [3H]-cholesterol levels at indicated time points and (D) fecal [3H]-sterol levels (0–48 hr) from a macrophage-to-feces RCT study performed in Alox5+/+ and Alox5−/− mice (n = 3).(E) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 4; bars represent densitometric quantification normalized to actin). Graphs show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.(F) Mediator lipidomics in livers of Alox5+/+ and Alox5−/− mice (n = 3). Graphs show mean ± SEM.

Mentions: Next, we wondered whether knocking out Alox5 would affect hepatic Abcb11 expression, cholesterol homeostasis, and RCT in mice (Figure 5A). As shown in Figure 5B, no marked difference in plasma LDL-C and HDL-C between Alox5+/+ and Alox5−/− mice was observed, whereas VLDL-C levels increased in the knockouts. In macrophage-to-feces RCT experiments, Alox5−/− mice showed reduced plasma tracer levels over 48 hr (Figure 5C) but no significant change in fecal excretion of [3H]-sterols, when compared to Alox5+/+ mice (Figure 5D). Immunoblot analysis revealed an ∼2-fold induction of hepatic Abcb11 and a moderate increase in SR-BI, but no effect on LDLr protein expression (Figure 5E). Finally, lipidomic profiling of livers from Alox5+/+ and Alox5−/− mice showed no changes in LX levels, whereas LTB4 levels were drastically reduced (Figure 5F).


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)

The Role of Alox5 in Abcb11 Regulation and Cholesterol Homeostasis(A) To selectively study the Alox5 pathway, studies in Alox5+/+ and Alox5−/− mice were performed.(B) FPLC analysis of plasma pooled from Alox5+/+ and Alox5−/− mice (n = 5).(C) Plasma [3H]-cholesterol levels at indicated time points and (D) fecal [3H]-sterol levels (0–48 hr) from a macrophage-to-feces RCT study performed in Alox5+/+ and Alox5−/− mice (n = 3).(E) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 4; bars represent densitometric quantification normalized to actin). Graphs show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.(F) Mediator lipidomics in livers of Alox5+/+ and Alox5−/− mice (n = 3). Graphs show mean ± SEM.
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fig5: The Role of Alox5 in Abcb11 Regulation and Cholesterol Homeostasis(A) To selectively study the Alox5 pathway, studies in Alox5+/+ and Alox5−/− mice were performed.(B) FPLC analysis of plasma pooled from Alox5+/+ and Alox5−/− mice (n = 5).(C) Plasma [3H]-cholesterol levels at indicated time points and (D) fecal [3H]-sterol levels (0–48 hr) from a macrophage-to-feces RCT study performed in Alox5+/+ and Alox5−/− mice (n = 3).(E) Immunoblot analysis of LDLr, SR-BI, and Abcb11 protein expression in livers of mice (n = 4; bars represent densitometric quantification normalized to actin). Graphs show mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.(F) Mediator lipidomics in livers of Alox5+/+ and Alox5−/− mice (n = 3). Graphs show mean ± SEM.
Mentions: Next, we wondered whether knocking out Alox5 would affect hepatic Abcb11 expression, cholesterol homeostasis, and RCT in mice (Figure 5A). As shown in Figure 5B, no marked difference in plasma LDL-C and HDL-C between Alox5+/+ and Alox5−/− mice was observed, whereas VLDL-C levels increased in the knockouts. In macrophage-to-feces RCT experiments, Alox5−/− mice showed reduced plasma tracer levels over 48 hr (Figure 5C) but no significant change in fecal excretion of [3H]-sterols, when compared to Alox5+/+ mice (Figure 5D). Immunoblot analysis revealed an ∼2-fold induction of hepatic Abcb11 and a moderate increase in SR-BI, but no effect on LDLr protein expression (Figure 5E). Finally, lipidomic profiling of livers from Alox5+/+ and Alox5−/− mice showed no changes in LX levels, whereas LTB4 levels were drastically reduced (Figure 5F).

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