Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation

Abstract

Aims While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAGcatabolizing enzymes such as adipose triglyceride lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor a (PPARa) activity and subsequent fatty acid oxidation (FAO).However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARa activity, cardiac function, and metabolism is not known. Methods and results To study the effects of acquired cardiac ATGL deficiency on cardiac PPARa activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (icAtglKO).Within 4-6 weeks following ATGL ablation, icAtglKO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in icAtglKOmice. Analysis of energy metabolism in ex vivo perfused working hearts showed diminished FAOrates which was not paralleled by markedly impaired PPARa target gene expression. Conclusions This study showsthat acquired cardiomyocyte-specificATGLdeficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARa signalling.