Targeting macrophage metabolism improves atherosclerosis outcome

Given the prominent role of macrophages in the progression of atherosclerosis, modulating their responses is considered as a promising strategy to treat atherosclerosis. Recent literature revealed an important role for ATP citrate lyase (Acly) in translating metabolic changes into altered macrophage phenotype and function.
Serving as a link between carbohydrate and lipid metabolism makes Acly a promising target to lower low-density lipoprotein (LDL) cholesterol levels and to reduce cardiovascular risk. Bempedoic acid is a competitive Acly inhibitor that is specifically activated in hepatocytes where it upregulates LDL receptor. Although promising data from clinical trials highlight that hepatic Acly inhibition reduces LDL cholesterol levels in hypercholesterolemic patients, the tools to study this key metabolic hub in macrophages in vivo remained absent.

To tackle this important question, we generated a new genetic knockout mouse model that specifically lacks Acly in macrophages and found that Acly deficiency in myeloid cells induces a stable plaque phenotype. The favorable plaque phenotype was linked to deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages. This resulted in macrophage apoptosis, along with more efficient efferocytosis and increased clearance of apoptotic cells. As such, we showed that targeting macrophage Acly improves atherosclerosis outcome in mice and can serve as a promising therapeutic target to stabilize atherosclerotic plaques.

Potential relevance for the clinic is supported by the observation that Acly is activated in inflammatory macrophages and in unstable human atherosclerotic plaques. An important next translational step is to test whether bempedoic acid or other Acly inhibitors also yield beneficial macrophage and plaque phenotypes in cardiovascular patients.