Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis
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作者:
Pinkosky, Stephen L.
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Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Pinkosky, Stephen L.
[1
,2
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Newton, Roger S.
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Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USAEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Newton, Roger S.
[1
]
Day, Emily A.
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McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Day, Emily A.
[2
]
Ford, Rebecca J.
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McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Ford, Rebecca J.
[2
]
Lhotak, Sarka
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McMaster Univ, St Josephs Healthcare Hamilton, Dept Med, 50 Charlton Ave East, Hamilton, ON L8N 4A6, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Lhotak, Sarka
[3
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Austin, Richard C.
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McMaster Univ, St Josephs Healthcare Hamilton, Dept Med, 50 Charlton Ave East, Hamilton, ON L8N 4A6, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Austin, Richard C.
[3
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Birch, Carolyn M.
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Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USAEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Birch, Carolyn M.
[1
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Smith, Brennan K.
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McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Smith, Brennan K.
[2
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Filippov, Sergey
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Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USAEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Filippov, Sergey
[1
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Groot, Pieter H. E.
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Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USAEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Groot, Pieter H. E.
[1
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Steinberg, Gregory R.
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McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, Canada
McMaster Univ, Dept Biochem & Biomed Sci, 1280 Main St West, Hamilton, ON L8S 4K1, CanadaEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Steinberg, Gregory R.
[2
,4
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Lalwani, Narendra D.
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Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USAEsper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
Lalwani, Narendra D.
[1
]
机构:
[1] Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA
[2] McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, Canada
[3] McMaster Univ, St Josephs Healthcare Hamilton, Dept Med, 50 Charlton Ave East, Hamilton, ON L8N 4A6, Canada
[4] McMaster Univ, Dept Biochem & Biomed Sci, 1280 Main St West, Hamilton, ON L8S 4K1, Canada
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.
机构:
Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Stanford Univ, Dept Med, Stanford, CA 94305 USAVet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Shende, Vikram Ravindra
Wu, Minhao
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Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USAVet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Wu, Minhao
Singh, Amar Bahadur
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Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Stanford Univ, Dept Med, Stanford, CA 94305 USAVet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Singh, Amar Bahadur
Dong, Bin
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Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USAVet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Dong, Bin
Kan, Chin Fung Kelvin
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Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USAVet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
Kan, Chin Fung Kelvin
Liu, Jingwen
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Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USAVet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA