Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
AstraZeneca Gothenburg, Biopharmaceuticals R&D, Mӧlndal, Sweden.
FASEB J. 2021 Nov;35(11):e21976. doi: 10.1096/fj.202100380RRR.
Fibrates and omega-3 polyunsaturated acids are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study, we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid-lowering agents. Plasma from overweight patients with non-alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, participating in a randomized placebo-controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega-3 free carboxylic acids (OM-3CA) (200 mg or 4 g per day, respectively), were analyzed for eicosanoids and related PUFA species, N-acylethanolamines (NAE) and ceramides. OM-3CA reduced plasma concentrations of proinflammatory PGE , as well as PGE , PGD and thromboxane B2 but increased prostacyclin, and eicosapentaenoic acid- and docosahexaenoic acid-derived lipids of lipoxygenase and cytochrome P450 monooxygenase (CYP) (e.g., 17-HDHA, 18-HEPE, 19,20-DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP-derived eicosanoids (DHETs). Although OM-3CA increased plasma levels of the NAE docosahexaenoyl ethanolamine and docosapentaenoyl ethanolamine, and fenofibrate increased palmitoleoyl ethanolamine, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM-3CA in significantly reducing plasma ceramides, pro-inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM-3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM-3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction.
贝特类药物和 ω-3 多不饱和脂肪酸用于治疗高三酰甘油血症，但它们对心血管（CV）风险的影响并不一致。在这项研究中，我们研究了这两种药物如何影响生物活性脂质介质的血浆水平，旨在探索它们除了降脂药物之外的疗效。我们分析了超重的非酒精性脂肪性肝病（NAFLD）和高三酰甘油血症患者的血浆，这些患者参与了一项随机安慰剂对照研究，研究了 12 周芬诺贝特或 ω-3 游离羧酸（OM-3CA）治疗（每天分别为 200mg 或 4g）的效果，分析了类二十烷酸和相关多不饱和脂肪酸（PUFA）种类、N-酰基乙醇胺（NAE）和神经酰胺。OM-3CA 降低了促炎 PGE 的血浆浓度，以及 PGE 、PGD 和血栓素 B2，但增加了前列腺素，以及脂氧合酶和细胞色素 P450 单加氧酶（CYP）衍生的二十碳五烯酸和二十二碳六烯酸脂质（例如，17-HDHA、18-HEPE、19,20-DiHDPA）。非诺贝特降低了血管活性 CYP 衍生的类二十烷酸（DHETs）的血浆浓度。虽然 OM-3CA 增加了 NAE 二十二碳六烯酰乙醇胺和二十二碳五烯酰乙醇胺的血浆水平，而非诺贝特增加了棕榈油酸乙醇胺，但两种治疗的效果可能被安慰剂（橄榄油）掩盖了。非诺贝特比 OM-3CA 更有效地显著降低血浆神经酰胺和与 CV 疾病风险相关的促炎脂质。两种治疗都没有影响与 NAFLD 相关的假定脂质种类。我们的结果表明，OM-3CA 和非诺贝特以不同的方式调节血浆介质脂质组，OM-3CA 促进潜在影响慢性炎症的脂质介质的形成，而非诺贝特主要减少神经酰胺。这些发现表明，这两种治疗都可以改善慢性炎症，可能对疾病结局产生影响，而不依赖于甘油三酯的降低。
