Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.
Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.
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DOI：
10.1038/ncomms13457
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发表时间：
2016-11-28
影响因子：
16.6
通讯作者：
Lalwani, Narendra D.
中科院分区：
文献类型：
--
作者：
Pinkosky, Stephen L.;Newton, Roger S.;Day, Emily A.;Ford, Rebecca J.;Lhotak, Sarka;Austin, Richard C.;Birch, Carolyn M.;Smith, Brennan K.;Filippov, Sergey;Groot, Pieter H. E.;Steinberg, Gregory R.;Lalwani, Narendra D.
尽管广泛使用他汀类药物来降低低密度脂蛋白胆固醇 (LDL-C) 和相关的动脉粥样硬化心血管风险，但由于肌肉相关的副作用，许多患者未能实现足够的 LDL-C 降低，这表明需要新的治疗策略。 Bempedoic Acid (ETC-1002) 是一种小分子，旨在降低高胆固醇血症患者的 LDL-C，之前已被证明可以调节啮齿动物的 ATP-柠檬酸裂解酶 (ACL) 和 AMP 激活蛋白激酶 (AMPK) 活性。然而，其降低 LDL-C 的机制、在动脉粥样硬化模型中的功效以及在人类中的相关性尚不清楚。在此，我们证明 ETC-1002 是一种前药，需要被极长链酰基辅酶 A 合成酶 1 (ACSVL1) 激活才能调节两个靶点，并且抑制 ACL 会导致 LDL 受体上调、LDL-C 降低和动脉粥样硬化减弱，与 AMPK 无关。此外，我们证明骨骼肌中 ACSVL1 的缺失为 ETC-1002 提供了潜在避免与他汀类药物治疗相关的肌肉毒性的机制基础。 他汀类药物是预防心血管疾病的降脂药物，但其耐受性受到肌肉严重副作用的限制。在这里，作者阐明了 Bempedoic Acid（一种新型降胆固醇药物）的肝脏特异性激活机制，并展示了它如何有效降低小鼠的 LDL-C 和动脉粥样硬化负担，但不会引起肌肉毒性。
Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy. Statins are lipid-lowering drugs that prevent cardiovascular disease but tolerability is limited by severe side effects in muscles. Here the authors elucidate a liver-specific activation mechanism for bempedoic acid, a novel cholesterol-lowering drug, and show how it effectively reduces LDL-C and atherosclerotic burden in mice, but does not cause myotoxicty.
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影响因子：
7.3
作者：
DOLLE, RE;MCNAIR, D;GROOT, PHE
通讯作者：
GROOT, PHE
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
37.8
作者：
Bellosta, S;Paoletti, R;Corsini, A
通讯作者：
Corsini, A
影响因子：
8.9
作者：
Grevengoed TJ;Klett EL;Coleman RA
通讯作者：
Coleman RA
影响因子：
--
作者：
Hardie DG;Ross FA;Hawley SA
通讯作者：
Hawley SA