Lactate promotes macrophage-derived foam cell formation and atherosclerosis

Diabetes accelerates atherosclerosis progression by disrupting multiple metabolic pathways. However, the role and mechanisms of lactate-a glycolytic byproduct significantly elevated in diabetic patients-in atherosclerosis remain poorly understood. We hypothesized that lactate promotes atherosclerosis by regulating macrophage foam cell formation through histone lactylation.

We evaluated the association between lactate levels, lipid metabolism disorders, and atherosclerotic progression using clinical samples and mouse models. The thoracic aortas of atherosclerotic mice were subjected to ex vivo culture to investigate the impact of lactate on the microenvironment within atherosclerotic plaques. Foam cell models were established using human and murine macrophages, and intracellular lipid accumulation, inflammatory responses, and apoptosis were assessed following lactate treatment. RNA sequencing was performed to dissect the molecular mechanisms underlying lactate-induced foam cell formation.

Results demonstrated that lactate promoted foam cell formation and contributed to atherosclerotic progression by enhancing intracellular lipid accumulation, pro-inflammatory cytokine secretion, and apoptosis in macrophages. RNA-seq analysis revealed that lactate significantly modulated pathways related to atherosclerosis and lipid metabolism, specifically inhibiting cholesterol efflux pathways during foam cell formation. Lactate increased H3K18la enrichment at the promoters of cholesterol efflux genes, accompanied by reduced expression of ABCA1, ABCG1, and SR-B1 and enhanced lipid accumulation. Notably, magnesium ions attenuated these lactate-associated effects and reduced intracellular lactate accumulation in macrophages.

Lactate contributes to atherosclerosis progression by enhancing foam cell formation and histone lactylation in macrophages, an effect mitigated by Mg²⁺. These findings identify lactate as a potential contributor to atherosclerosis progression and provide mechanistic insights into lactate-associated metabolic regulation in macrophages.