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Learn MoreLoss of TFEB action, impaired lysosomal autophagy and increased proteotoxicity are observed in numerous metabolic diseases. Previous research from our laboratory demonstrated that glucolipotoxicity following nutrient-overload causes cardiomyocyte injury by inhibiting TFEB and suppressing lysosomal function. However, the identity of signalling and metabolic pathways engaged by the loss of TFEB action in the cardiomyocytes remain unknown. In cardiomyocytes subjected to nutrient-overload ex-vivo, saturated fatty acid, palmitate, but not polyunsaturated fatty acids decreased TFEB content in a concentration- and time-dependent manner. Hearts from high-fat high-sucrose diet-fed mice also exhibited a temporal decline in nuclear TFEB content with marked elevation of distinct lipid species suggesting that when myocyte threshold of lipid loading exceeds its metabolic capacity, loss of TFEB and cardiomyocyte stress is observed. Transcriptome analysis in murine cardiomyocytes with targeted deletion of myocyte TFEB (TFEB-/-) revealed enrichment of differentially expressed genes (DEG) representing pathways of nutrient metabolism, DNA damage and repair, cell death and cardiac function. Strikingly, genes involved in autophagy, proteolysis and lysosome function constituted a small portion of DEGs in TFEB-/- cardiomyocytes signifying that TFEB plausibly regulates non-canonical pathways of cardiac energy metabolism than the canonical pathway of autophagy. TFEB-/- myocytes exhibited higher lipid droplet accumulation and increased caspase-3 activation. Under nutrient-overload condition, restoration of constitutive localization of TFEB in the myocyte nucleus abrogated increased lipid deposition and caspase-3 activity. Together, our data demonstrated that TFEB insufficiency and its loss of action in the cardiomyocyte remodels energy metabolism and renders the heart prematurely susceptible to nutrient overload-induced injury and failure. SOURCE: Thomas Pulinilkunnil (tpulinil@dal.ca) - Nutrient Signaling Metabolism Laboratory Dalhousie University
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