FASN is upregulated in arrhythmogenic cardiomyopathy, leading to ceramide-induced cardiomyocyte apoptosis, and its inhibition with orlistat mitigates the ACM phenotype in Dsg2mut/mut mice.
Does FASN inhibition with orlistat mitigate the arrhythmogenic cardiomyopathy phenotype in Dsg2mut/mut mice?
FASN-mediated lipotoxicity drives cardiomyocyte apoptosis in arrhythmogenic cardiomyopathy, and pharmacological inhibition of FASN represents a potential novel therapeutic strategy.
Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a hereditary cardiomyopathy associated with desmosomal gene mutations. Its pathology is characterized by the progressive replacement of ventricular myocardium with fibrofatty tissue, particularly affecting the right ventricle. Fatty acid synthase (FASN), the rate-limiting enzyme in de novo lipogenesis, plays a crucial role in converting glucose intermediates into fatty acids. However, its role in ACM remains poorly understood. Purpose We aim to investigate whether FASN-mediated de novo lipogenesis and related lipotoxicity are promoted in cardiomyocytes of ACM patients, leading to cardiomyocyte damage and triggering apoptosis. Methods FASN expression in right ventricle tissue from ACM patients and healthy controls was investigated using western blot and immunohistochemistry. DNA pull-down assays, dual luciferase reporter assays, and Duolink proximity ligation assays were employed to explore the mechanism underlying FASN upregulation. We performed 13C glucose isotope tracing experiments and mass spectrometry for metabolic characterization. Additionally, lipid profiling was conducted on heart tissues and blood samples from ACM patients. The therapeutic potential of inhibiting FASN was tested in Dsg2mut/mut mice via intraperitoneal administration of the FASN inhibitor orlistat. Results FASN is upregulated in cardiomyocytes from both human ACM samples and Dsg2mut/mut mice. We found that the nuclear translocation of junction plakoglobin and its interaction with SREBP1 activate the transcription of FASN gene, which promotes de novo lipogenesis in cardiomyocytes. Further analysis revealed that the newly synthesized fatty acids are converted to ceramides, which induce cardiomyocyte toxicity and trigger apoptosis. Finally, intraperitoneal administration of the FASN inhibitor orlistat mitigates the ACM phenotype in Dsg2mut/mut mice. Conclusions FASN is specifically upregulated in cardiomyocytes in ACM, leading to the accumulation of fatty acids and cardiomyocyte apoptosis. FASN represents a potential therapeutic target for ACM.
Liu et al. (Sat,) conducted a other in Arrhythmogenic cardiomyopathy. Orlistat (FASN inhibitor) was evaluated on ACM phenotype mitigation and FASN expression. FASN is upregulated in arrhythmogenic cardiomyopathy, leading to ceramide-induced cardiomyocyte apoptosis, and its inhibition with orlistat mitigates the ACM phenotype in Dsg2mut/mut mice.