Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis.
Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis.
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DOI：
10.1097/mol.0000000000000215
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发表时间：
2015-10
影响因子：
4.4
通讯作者：
Brown JM
中科院分区：
文献类型：
--
作者：
Schugar RC;Brown JM
动脉粥样硬化和相关的心血管疾病(CVD)仍然是全球范围内死亡的最大原因。最近的几项研究发现，肠道微生物对常见营养物质的新陈代谢可以产生一种称为三甲胺-N-氧化物(TMAO)的致动脉粥样硬化代谢物。这篇综述的目的是讨论新的证据，即产生TMAO的肝酶，黄素单加氧酶3(FMO3)，在维持全身胆固醇平衡和动脉粥样硬化的发展中发挥调节作用。最近几项独立研究发现，FMO3本身或其酶产物TMAO与动脉粥样硬化和肝脏胰岛素抵抗之间存在联系。这些最近的研究表明，抑制FMO3可以刺激巨噬细胞胆固醇逆向运输(RCT)，并保护小鼠免受动脉粥样硬化的影响。越来越多的研究表明，高脂肪食物中的营养物质(磷脂酰胆碱、胆碱和L肉碱)可以被肠道微生物酶代谢产生三甲胺，然后由宿主酶FMO3进一步代谢产生致动脉粥样硬化的TMAO。在这里，我们讨论新的证据，即TMAO产生酶FMO3通过调节胆固醇代谢和胰岛素抵抗而在动脉粥样硬化的发病机制中发挥核心作用，以及这些新的见解如何为心血管疾病的治疗提供令人兴奋的新途径。
Atherosclerosis and associated cardiovascular disease (CVD) still remain the largest cause of mortality worldwide. Several recent studies have discovered that metabolism of common nutrients by gut microbes can produce a proatherogenic metabolite called trimethylamine-N-oxide (TMAO). The goal of this review is to discuss emerging evidence that the hepatic enzyme that generates TMAO, flavin monooxygenase 3 (FMO3), plays a regulatory role in maintaining whole body cholesterol balance and atherosclerosis development. Several independent studies have recently uncovered a link between either FMO3 itself or its enzymatic product TMAO with atherosclerosis and hepatic insulin resistance. These recent studies show that inhibition of FMO3 stimulates macrophage reverse cholesterol transport (RCT) and protects against atherosclerosis in mice. A growing body of work demonstrates that nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme FMO3 to produce proatherogenic TMAO. Here we discuss emerging evidence that the TMAO producing enzyme FMO3 is centrally involved in the pathogenesis of atherosclerosis by regulating cholesterol metabolism and insulin resistance, and how these new insights provide exciting new avenues for CVD therapies.