Aerobic exercise reduces lipid accumulation via ACLY-mediated metabolic remodeling to alleviate cardiac remodeling

Pathological cardiac remodeling, a key contributor to heart failure, is characterized by significant reprogramming of cardiac energy metabolism. ATP-citrate lyase (ACLY), which connects glucose metabolism with lipid synthesis, plays an important regulatory role in this process. However, the role of ACLY in exercise-induced metabolic remodeling and cardiac remodeling attenuation remains unclear.

Cardiac remodeling was induced in H9c2 cells with isoproterenol or urea, or in rats by left anterior descending artery (LAD) ligation or mice by isoproterenol. Interventions included ACLY knockdown, bempedoic acid, or exercise (8/16 wk). Outcomes were assessed via echocardiography, histology, immunohistochemistry, immunofluorescence, and Western blotting.

ACLY was significantly upregulated in cellular and animal models of cardiac remodeling and correlated with cardiomyocyte hypertrophy and lipid accumulation. ACLY knockdown or bempedoic acid treatment attenuated hypertrophy, reduced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and inhibited lipogenesis. Aerobic exercise was associated with attenuated cardiac remodeling, accompanied by downregulation of ACLY, acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN), and reduced myocardial lipid deposition, with a more pronounced effect observed after 16 weeks than after 8 weeks of training.

Aerobic exercise was associated with downregulation of ACLY and reduced myocardial lipogenesis, which may contribute to the attenuation of structural and functional remodeling. This study suggests that the cardioprotective effects of exercise are associated with regulation of lipid metabolism.