Adenosine Triphosphate ATP Citrate Lyase ACL Inhibitors Hypocholesterolemic Agents

Hypocholesterolemic Agents: Adenosine Triphosphate (ATP) Citrate Lyase (ACL) Inhibitors

By limiting cholesterol synthesis in the liver, ATP-citrate lyase (ACL) inhibitors reduce LDLc. The enzyme ACL is upstream of HMG-CoA reductase in the cholesterol production pathway. Bempedoic acid is a novel and, until now, the only licensed adenosine triphosphate citrate lyase inhibitor that operates through the cholesterol-synthesis pathway (much like statins) to reduce LDL-C safely and effectively (Brandts & Ray, 2020). Because it is a prodrug, it is activated in the hepatocyte, avoiding the muscular side effects that statins might cause.

ACL as compared to Statins

i. Mechanism of action

ACL is a non-mitochondrial enzyme abundant in lipogenic tissues like the liver and adipose tissue. ACL catalyzes the conversion of cytosolic Acetyl-CoA and oxaloacetate from mitochondrial-derived citrate, with Acetyl-CoA acting as a common substrate for de-novo cholesterol and fatty acid synthesis (Govindaraju & Sabarathinam, 2021). The sterol regulatory element-binding protein-1 (SREBP-1) regulates ACL transcription and is particularly responsive to dietary status via insulin signaling and glucose metabolites. ACL expression and cytosolic citrate levels are enhanced in the lipogenic state, and they serve as a crucial connection between glycolysis and lipid production and storage. Due to its strategic position in cholesterol manufacturing pathways, ACL inhibition is considered an appealing treatment option for lowering increased LDL-C levels.

On the other hand, statins, which are highly powerful and selective inhibitors of HMG-CoA reductase, block de-novo hepatic cholesterol synthesis, which is an effective treatment method for lowering LDL-C. Compensation upregulation of sterol regulatory element-binding protein-2 (SREBP2)-dependent gene transcription in response to reduced intracellular cholesterol levels is the major mechanism linking inhibition of hepatic sterol production to decreases in LDL-C (Govindaraju & Sabarathinam, 2021). Increases in cholesterogenic enzymes and elevation of LDL receptor expression are triggered when SREBP-2 activity is increased, resulting in a transcriptional program to restore intracellular cholesterol.

ii. Efficiency

Clinical trials have demonstrated that bempedoic acid reduces LDL-C levels in statin-intolerant patients as a monotherapy, combination therapy, or as an add-on to statin therapy. More recently, the CLEAR Harmony phase 3 clinical trial (“Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol”) found that bempedoic acid decreases LDL-C levels in hypercholesterolemic individuals taking guideline-recommended statin therapy while maintaining a favorable safety profile (Feng et al., 2020).

Non-HDL-C levels are also significantly reduced by statins (LDL-C is the major contributor to non-HDL-C levels). Statins also reduce triglyceride levels in the blood. Statins’ ability to decrease triglyceride levels is linked to a drop in LDL-C. The most effective statins for lowering LDL-C are likewise the most effective for lowering plasma triglyceride and VLDL-C levels (Feingold, 2021).

iii. Side effects