Despite overwhelming evidence from large randomized clinical trials supporting a clear benefit of low-density lipoprotein cholesterol(LDL-C)lowering therapy on the primary and secondary prevention of atherosclerotic c...Despite overwhelming evidence from large randomized clinical trials supporting a clear benefit of low-density lipoprotein cholesterol(LDL-C)lowering therapy on the primary and secondary prevention of atherosclerotic cardiovascular disease,data from epidemiological and clinical observations demonstrated an increased incidence of hemorrhagic stroke in patients with low LDL-C exposure(<70 mg/dL),especially among East Asians.Meanwhile,emerging studies have reported a paradoxical phenomenon in which hypercholesterolemia is associated with better short-term outcomes in acute coronary syndrome patients,the"lipid paradox."The underlying mechanism for these two closely connected clinical observations is not clear.This review aimed to summarize the evolution and clinical implications of these two low LDL-C related concepts,and proposed a"double-hit"hypothesis that may help explain these phenomena.It is worth noting that in the era of increasing use of high-intensity LDL-C lowering and dual antiplatelet strategies in atherosclerotic cardiovascular disease in patients receiving percutaneous coronary intervention,balancing the risk of thrombosis with bleeding complication should be a priority in clinical practice.Our hypothesis may raise clinicians’awareness to identify potential high risk patients with low LDL-C(<70 mg/dL),especially among East Asians.展开更多
脂滴包被蛋白5(perilipin5,Plin5)在脂肪酸氧化程度较高的组织中表达,虽然在细胞和动物模型中均发现Plin5具有促进脂滴堆积、提高线粒体功能和缓解脂毒性的作用,但Plin5如何发挥其功能特点的具体机制尚未得到分析整合。通过分析相关文...脂滴包被蛋白5(perilipin5,Plin5)在脂肪酸氧化程度较高的组织中表达,虽然在细胞和动物模型中均发现Plin5具有促进脂滴堆积、提高线粒体功能和缓解脂毒性的作用,但Plin5如何发挥其功能特点的具体机制尚未得到分析整合。通过分析相关文献发现:Plin5可以通过和CGI-58(comparative gene identification-58)结合来调节关键脂解酶脂肪甘油三酯水解酶(adiposetiglyceridelipase,ATGL)以调控脂肪的代谢过程;通过核转位与沉默信息调节因子2相关酶1(silent mating type information regulator 2homolog 1,SIRT1)和过氧化物酶体增殖物激活受体γ辅激活因子1α(PPARγcoactivator-1α,PGC-1α)结合促进线粒体功能基因的表达,提高线粒体的氧化能力和呼吸功能;通过增加围脂滴线粒体的含量促使脂滴含量增加并增强线粒体功能,这揭示了Plin5参与调节脂代谢和线粒体功能的具体机制。而耐力运动锻炼会显著增加Plin5的含量,表明Plin5是解释"运动员悖论"现象的关键因子,这为Plin5作为新的2型糖尿病治疗靶点提供了理论依据。展开更多
基金supported by the National Natural Science Foundation of China(Nos.81570335,81970304)a grant from Tianjin Municipal Science and Technology Commission,China(No.18ZXZNSY00290)
文摘Despite overwhelming evidence from large randomized clinical trials supporting a clear benefit of low-density lipoprotein cholesterol(LDL-C)lowering therapy on the primary and secondary prevention of atherosclerotic cardiovascular disease,data from epidemiological and clinical observations demonstrated an increased incidence of hemorrhagic stroke in patients with low LDL-C exposure(<70 mg/dL),especially among East Asians.Meanwhile,emerging studies have reported a paradoxical phenomenon in which hypercholesterolemia is associated with better short-term outcomes in acute coronary syndrome patients,the"lipid paradox."The underlying mechanism for these two closely connected clinical observations is not clear.This review aimed to summarize the evolution and clinical implications of these two low LDL-C related concepts,and proposed a"double-hit"hypothesis that may help explain these phenomena.It is worth noting that in the era of increasing use of high-intensity LDL-C lowering and dual antiplatelet strategies in atherosclerotic cardiovascular disease in patients receiving percutaneous coronary intervention,balancing the risk of thrombosis with bleeding complication should be a priority in clinical practice.Our hypothesis may raise clinicians’awareness to identify potential high risk patients with low LDL-C(<70 mg/dL),especially among East Asians.
文摘脂滴包被蛋白5(perilipin5,Plin5)在脂肪酸氧化程度较高的组织中表达,虽然在细胞和动物模型中均发现Plin5具有促进脂滴堆积、提高线粒体功能和缓解脂毒性的作用,但Plin5如何发挥其功能特点的具体机制尚未得到分析整合。通过分析相关文献发现:Plin5可以通过和CGI-58(comparative gene identification-58)结合来调节关键脂解酶脂肪甘油三酯水解酶(adiposetiglyceridelipase,ATGL)以调控脂肪的代谢过程;通过核转位与沉默信息调节因子2相关酶1(silent mating type information regulator 2homolog 1,SIRT1)和过氧化物酶体增殖物激活受体γ辅激活因子1α(PPARγcoactivator-1α,PGC-1α)结合促进线粒体功能基因的表达,提高线粒体的氧化能力和呼吸功能;通过增加围脂滴线粒体的含量促使脂滴含量增加并增强线粒体功能,这揭示了Plin5参与调节脂代谢和线粒体功能的具体机制。而耐力运动锻炼会显著增加Plin5的含量,表明Plin5是解释"运动员悖论"现象的关键因子,这为Plin5作为新的2型糖尿病治疗靶点提供了理论依据。
