The multifaceted therapeutic value of targeting ATP-citrate lyase in atherosclerosis

Verberk, Sanne G.S.; Kuiper, Kirsten L.; Lauterbach, Mario A.; Latz, Eicke; Bossche, Jan Van den

doi:10.1016/j.molmed.2021.09.004

Cited by 22 publications

(18 citation statements)

References 81 publications

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“…In a mouse model of diet-induced obesity, bempedoic acid restored adipose AMPK activity, decreased adipose tissue inflammation and reduced interleukin-6 synthesis ( 24 ). Additionally, inhibition of ACLY by bempedoic acid reduced prostaglandin E2 production and contributed to decrease the inflammatory response ( 25 ).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Biolo

Vinci

Mangogna

et al. 2022

Front. Cardiovasc. Med.

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Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Biolo

Vinci

Mangogna

et al. 2022

Front. Cardiovasc. Med.

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“…Another proposed mechanism is the downregulation of inflammatory signalling pathways through AMP kinase activation [ 33 ]. Additionally, inhibition of ACLY by bempedoic acid has been demonstrated to reduce prostaglandin production and contribute to anti-inflammatory action [ 34 ] and may have some role in NASH as well [ 35 ]. Lauf et al., in their CLEAR Serenity study, showed that bempedoic acid was associated with a 24.3% reduction in hsCRP levels from baseline, reducing inflammation and possibly ASCVD risk [ 36 ].…”

Section: Bempedoic Acid Ameliorates Inflammationmentioning

confidence: 99%

Bempedoic acid and its role in contemporary management of hyperlipidemia in atherosclerosis

et al. 2022

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Atherosclerotic heart disease is the leading cause of mortality and morbidity in the USA. Low density lipoprotein (LDL) has been the target for many hypolipidemic agents to modify atherosclerotic risk. Bempedoic acid is a novel hypolipidemic drug that inhibits the enzymatic activity of ATP citrate lyase in the cholesterol synthesis pathway. CLEAR Harmony, CLEAR Wisdom, CLEAR Tranquillity and CLEAR Serenity have shown safety and efficacy associated with long term administration of this drug. Studies have shown effectiveness in reducing LDL-C in both statin intolerant patients and in patients on maximally tolerated doses of statin. The fixed drug combination of bempedoic acid and ezetimibe in a recent phase III showed significant reduction in LDL compared with placebo, which might be a promising future for LDL reduction among statin intolerant patients. Bempedoic acid also reduced inflammatory markers like hs-CRP. Given these results, bempedoic acid alone and in combination with ezetimibe received the USA FDA approval for adults with heterozygous familial hypercholesterolaemia or established atherosclerotic cardiovascular disease. We present a comprehensive review exploring the underlying mechanism, pre-clinical studies, and clinical trials of bempedoic acid and discuss the potential future role of the drug in treating hyperlipidaemia.

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“…In contrast to the phenotype of ACLY-deficient THP-1 cells or murine macrophages, studies using pharmacological inhibition or silencing of ACLY showed suppressed responses towards LPS stimulation linked to gene-specific inhibition of histone acetylation ( 12 , 13 , 35 ). Highlighted in a recent review, these discrepancies may reflect long-term adaptations to an ACLY loss as well as off-target effects of the inhibitors ( 36 ). Regarding the adaptive mechanisms, increased flux through acetate recycling by the action of ACSS2 can be a potential source of the maintained histone acetylation in ACLY knockout cell lines ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells

et al. 2022

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ATP-citrate lyase (ACLY) is a key enzyme provoking metabolic and epigenetic gene regulation. Molecularly, these functions are exerted by the provision of acetyl-coenzyme A, which is then used as a substrate for de novo lipogenesis or as an acetyl-group donor in acetylation reactions. It has been demonstrated that ACLY activity can be positively regulated via phosphorylation at serine 455 by Akt and protein kinase A. Nonetheless, the impact of phosphorylation on ACLY function in human myeloid cells is poorly understood. In this study we reconstituted ACLY knockout human monocytic THP-1 cells with a wild type ACLY as well as catalytically inactive H760A, and phosphorylation-deficient S455A mutants. Using these cell lines, we determined the impact of ACLY activity and phosphorylation on histone acetylation and pro-inflammatory gene expression in response to lipopolysaccharide (LPS). Our results show that ACLY serine 455 phosphorylation does not influence the proper enzymatic function of ACLY, since both, wild type ACLY and phosphorylation-deficient mutant, exhibited increased cell growth and histone acetylation as compared to cells with a loss of ACLY activity. Transcriptome analysis revealed enhanced expression of pro-inflammatory and interferon response genes in ACLY knockout and H760A THP-1 cells under unstimulated or LPS-treated conditions. At the same time, S455A ACLY-expressing cells showed a phenotype very similar to wild type cells. Contrary to ACLY knockout, pharmacological inhibition of ACLY in THP-1 cells or in primary human macrophages does not enhance LPS-triggered pro-inflammatory gene expression. Our data thus suggest that ACLY retains functionality in the absence of Akt/PKA-mediated phosphorylation in human myeloid cells. Furthermore, loss of ACLY activity may elicit long-term adaptive mechanisms, increasing inflammatory responses.

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The multifaceted therapeutic value of targeting ATP-citrate lyase in atherosclerosis

Cited by 22 publications

References 81 publications

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Bempedoic acid and its role in contemporary management of hyperlipidemia in atherosclerosis

Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells

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