ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia.
Curr Opin Lipidol
; 28(2): 193-200, 2017 Apr.
Article
em En
| MEDLINE
| ID: mdl-28059952
ABSTRACT
PURPOSE OF REVIEW ATP-citrate lyase (ACLY) has re-emerged as a drug target for LDL cholesterol (LDL-C) lowering. We review ACLY as a therapeutic strategy, its genetics, its molecular and cellular biology, and also its inhibition. RECENT FINDINGS:
ACLY is a critical enzyme linking glucose catabolism to lipogenesis by providing acetyl-CoA from mitochondrial citrate for fatty acid and cholesterol biosynthesis. Human genetic variants have been associated with enhanced growth and survival of several cancers, and with attenuated plasma triglyceride responses to dietary fish oil. In mice, liver-specific Acly deficiency protects from hepatic steatosis and dyslipidemia, whereas adipose tissue-specific Acly deletion has no phenotype, supporting therapeutic inhibition of ACLY. A lipid-regulating compound, bempedoic acid, was discovered to potently inhibit ACLY, and in animal models, it prevents dyslipidemia and attenuates atherosclerosis. Phase 2 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients.SUMMARY:
The efficacy of bempedoic acid as an LDL-C-lowering agent has validated ACLY inhibition as a therapeutic strategy. Positive results of phase 3 patient studies, together with long-term cardiovascular disease outcome trials, are required to establish ACLY as a major new target in cardiovascular medicine.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
ATP Citrato (pro-S)-Liase
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Dislipidemias
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Terapia de Alvo Molecular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Curr Opin Lipidol
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Canadá