Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis

Pinkosky, Stephen L.; Newton, Roger S.; Day, Emily; Ford, Rebecca J.; Lhoták, Šárka; Austin, Richard C.; Birch, Carolyn M.; Smith, Brennan K.; Filippov, Sergey; Groot, P.H.E.; Steinberg, Gregory R.; Lalwani, Narendra D.

doi:10.1038/ncomms13457

Cited by 368 publications

(255 citation statements)

References 68 publications

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“…ACLY has been considered an effective target for the treatment of diseases associated to disorders of lipid metabolism [13,33,46,47]. Thus, the knowledge of molecular mechanism of ACLY regulation at translational level, reported in the present study, provides new elements for therapeutic treatment of metabolic diseases.…”

Section: Discussionmentioning

confidence: 59%

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Siculella

Giannotti

Testini

et al. 2020

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5 untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed. Int. J. Mol. Sci. 2020, 21, 1206 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B). Int. J. Mol. Sci. 2020, 21, 1206 Then ACLY levels showed a constant increase, becoming about 3.5-fold greater than the control after 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B).

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Section: Discussionmentioning

confidence: 59%

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Siculella

Giannotti

Testini

et al. 2020

IJMS

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“…Bempedoic acid is, in fact, a pro-drug activated to the-CoA derivative in the liver by the very-long-chain acyl-CoA synthase 1 (ACSVL1). The active derivative inhibits ACL in the liver, whereas no conversion occurs in skeletal muscle, lacking ACSVL 1 (177 28.5% and -31%, respectively (181) ( Table 1). The long-term safety and efficacy of bempedoic acid as well as the CV outcomes are being evaluated in other 3 ongoing clinical trials (182).…”

Section: Bempedoic Acidmentioning

confidence: 99%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

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“…Bempedoic acid inhibits liver acid citrate lyase, the step preceding HMG-CoA reductase (the target of statin therapy) [43]. Bempedoic acid inhibits liver acid citrate lyase, the step preceding HMG-CoA reductase (the target of statin therapy) [43].…”

Section: Other Drugsmentioning

confidence: 99%

“…There are relatively few other lipid drugs in development. Bempedoic acid inhibits liver acid citrate lyase, the step preceding HMG-CoA reductase (the target of statin therapy) [43]. It is a moderate efficacy agent that reduces LDLcholesterol by~20% and adds to statins (except possibly at the highest doses) [44].…”

Section: Other Drugsmentioning

confidence: 99%

Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

Wierzbicki

2018

Diabet. Med.

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Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL-cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed. Most data have been accumulated with proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors, which reduce LDL-cholesterol by 50-55%. A large CVD outcome trial with evolocumab, in which 40% of participants had diabetes, achieved a LDL-cholesterol of 0.8 mmol/l and showed a consistent 20% relative risk reduction within 2 years, including in people with diabetes. Trials to increase HDL-cholesterol using cholesterol ester transfer protein (CETP) inhibitors have generally underwhelmed. Although anacetrapib reduced coronary ischaemic events by 7% in a population with chronic CVD, more expansive CVD endpoints were not improved. The complex nature of CETP inhibitor trial outcomes means that these compounds are not being developed further. Trials targeting inflammation-associated lipids have been generally unsuccessful but recent data on the interleukin-1B receptor antagonist canakinumab have shown a reduction in acute coronary intervention, validating this target although at the cost of increased infections. The ability to achieve low LDL-cholesterol with off-patent medications and the costs of novel therapies will confine the use of novel agents to subgroups of people at highest risk of CVD.

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Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis

Cited by 368 publications

References 68 publications

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

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