ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation

ATP citrate lyase (ACLY) is a key enzyme in de novo lipogenesis that generates acetyl-CoA from citrate. Although fatty acids are required for energy production and biomass synthesis in the heart, the regulatory mechanisms of ACLY-mediated de novo lipogenesis in pathological cardiac fibroblasts remain unknown. The aim of this study was to investigate the biological role of ACLY in cardiac remodeling. Adeno-associated virus serotype 9-mediated shRNA targeting Acly was intravenously injected into C57BL/6J male mice. The mice were subsequently continuously infused with a mixture of angiotensin II and phenylephrine. Cardiac phenotypes were evaluated via histological staining. Cell proliferation assays, stable isotope tracing with 13C-labeled glucose, and chromatin immunoprecipitation assays were performed using human cardiac fibroblasts. ACLY expression was upregulated in the heart sections of mice treated with angiotensin II/phenylephrine, in particular in fibrotic areas. Masson trichrome staining revealed that Acly gene silencing significantly reduced cardiac fibrosis in these mice. Both siRNA-mediated ACLY knockdown and pharmacological ACLY inhibition suppressed the proliferation and expression of fibrous proteins in cultured human cardiac fibroblasts stimulated with transforming growth factor-β. Mechanistically, ACLY inhibition reduced de novo lipogenesis, limiting the fatty acid supply essential for cellular growth and proliferation. It also decreased H3K9 and H3K27 acetylation, in addition to the presence of acetylated H3K9 and H3K27 at the promoter regions of fibrotic genes. Our findings demonstrate that ACLY plays an important role in maladaptive cardiac fibrosis. ACLY could be a novel therapeutic target to prevent the development of heart failure.