PDF(Pubmed)
Abstract：
Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.
摘要：
他汀类药物可降低血液胆固醇水平，以预防心血管疾病。女性比男性更容易经历他汀类药物不良反应，尤其是新发糖尿病（NOD）和肌肉无力。在这里，我们发现他汀类药物治疗的雌性小鼠的葡萄糖稳态受损和肌肉无力与ω-3脂肪酸水平降低有关。二十二碳六烯酸（DHA），受损的氧化还原色调，减少线粒体呼吸.通过服用鱼油作为DHA的来源，可以预防女性的他汀类药物不良反应。通过减少X染色体或Kdm5c基因的剂量，逃避X染色体失活，通常在女性中的表达水平高于男性。正如在雌性老鼠身上看到的，我们发现，服用他汀类药物后，女性的DHA水平比男性严重下降，DHA水平与葡萄糖水平呈负相关。此外，患有NOD的女性的诱导多能干细胞在用他汀类药物治疗时表现出线粒体功能受损，而来自男性的细胞却没有。这些研究确定X染色体剂量是他汀类药物不良反应的遗传风险因素，并建议补充DHA作为预防性联合治疗。
