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
Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
Department of Internal Medicine, Angiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
Cell Metab. 2014 Nov 4;20(5):787-798. doi: 10.1016/j.cmet.2014.09.004.
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.
胆固醇代谢与人类心血管疾病密切相关。饮食中补充包括花生四烯酸（AA）在内的ω-6多不饱和脂肪酸已被证明对血浆低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）有积极影响。然而，其潜在机制尚不清楚。通过整合来自对超过10万名欧洲血统个体的全基因组关联研究（GWAS）筛查数据、介质脂质组学以及小鼠功能验证研究，我们确定AA代谢组是胆固醇稳态的重要调节因子。阿司匹林对AA代谢的药理调节诱导了肝脏中白三烯（LTs）和脂氧素（LXs）的生成，从而增加了胆汁盐输出泵Abcb11的肝脏表达。Abcb11的诱导转化为增强的胆固醇逆向转运，这是HDL的一项关键功能。对生物活性AA衍生物的进一步表征确定了LX模拟物可降低血浆LDL-C。我们的结果确定AA代谢组为胆固醇代谢的保守调节因子，并确定AA衍生物是治疗人类心血管疾病的有前景的疗法。
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