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

Bempedoic acid targets ATP-citrate lyase (Acly) in the liver, thereby lowering low-density lipoprotein-cholesterol (LDL-C) and systemic inflammation. Acly is a metabolic enzyme at the crossroads between carbohydrate metabolism, lipid metabolism, and histone acetylation. Targeting Acly in macrophages yields additive therapeutic value to broaden the strategy from solely lipid-lowering to targeting inflammatory activation. ATP-citrate lyase (Acly) is the target of the new class low-density lipoprotein-cholesterol (LDL-C)-lowering drug bempedoic acid (BA). Acly is a key metabolic enzyme synthesizing acetyl-CoA as the building block of cholesterol and fatty acids. Treatment with BA lowers circulating lipid levels and reduces systemic inflammation, suggesting a dual benefit of this drug for atherosclerosis therapy. Recent studies have shown that targeting Acly in macrophages can attenuate inflammatory responses and decrease atherosclerotic plaque vulnerability. Therefore, it could be beneficial to extend the application of Acly inhibition from solely lipid-lowering by liver-specific inhibition to also targeting macrophages in atherosclerosis. Here, we outline the possibilities of targeting Acly and describe the future needs to translate these findings to the clinic. ATP-citrate lyase (Acly) is the target of the new class low-density lipoprotein-cholesterol (LDL-C)-lowering drug bempedoic acid (BA). Acly is a key metabolic enzyme synthesizing acetyl-CoA as the building block of cholesterol and fatty acids. Treatment with BA lowers circulating lipid levels and reduces systemic inflammation, suggesting a dual benefit of this drug for atherosclerosis therapy. Recent studies have shown that targeting Acly in macrophages can attenuate inflammatory responses and decrease atherosclerotic plaque vulnerability. Therefore, it could be beneficial to extend the application of Acly inhibition from solely lipid-lowering by liver-specific inhibition to also targeting macrophages in atherosclerosis. Here, we outline the possibilities of targeting Acly and describe the future needs to translate these findings to the clinic. the first enzyme in FAS, converting acetyl-CoA into malonyl-CoA. an enzyme that dictates energy homeostasis by regulating glucose and fatty acid metabolism when cellular energy is low. AMPK also dampens inflammatory responses and is a direct target of BA. the deposition of lipids on the arterial wall that subsequently attract and activate immune cells and form a lipid-rich plaque that is invaded by immune cells. A rupture may lead to coronary heart disease or stroke. a nucleocytosolic metabolic enzyme converting citrate into oxaloacetate and acetyl-CoA in an ATP-dependent manner. The enzyme is targeted by BA in liver cells for the treatment of hypercholesterolemia and becomes activated in macrophages upon stimulation. a drug that targets Acly specifically in the liver, where it aids the clearance of cholesterol from the circulation to treat hypercholesterolemia and atherosclerosis. circulating protein, produced in response to inflammation and outlining the degree of systemic inflammation. a class of diseases that involve the heart and the arteries, currently the leading cause of death globally. clearance of death or apoptotic cells by phagocytosis. a motif that can be added to small molecules to specifically target hepatocytes, monocytes, and macrophages. Hepatocyte-, monocyte- and macrophage-specific carboxylesterases can cleave ESMs into pharmacologically active cell-impermeable charged acids. the metabolic pathway in which fatty acids are synthesized from acetyl-CoA. macrophages that are typically present in atherosclerotic plaques that have accumulated lipids. macrophages cultured from human blood-derived monocytes, often used as an in vitro model to study the response of macrophages to a certain stimulus. signaling circulating cytokines secreted by immune cells dictating the reprogramming of other immune cells. LDLs transport cholesterol from the circulation to the liver in a phospholipid layer containing apolipoprotein B. Levels of LDL-C correlate with atherosclerotic plaque formation. Oxidative stress can lead to oxLDL particles that are important activators of macrophages during atherosclerosis. the receptor that recognizes LDL in the circulation and instructs the body for the recycling of LDL. The knockout of this receptor in mice leads to foam cell formation and is a model for atherosclerosis in combination with a high-fat diet. an enzyme involved in cholesterol metabolism, highly correlated with CVDs, that is targeted by novel antiatherosclerotic drugs to lower circulating cholesterol levels. cell wall component of Gram-negative bacteria. LPS stimulates cells via interaction with Toll-like receptor 4. a molecule designed to inhibit the functioning of a specific enzyme or transporter. profibrotic signaling cytokine that stimulates cells to produce collagen.