Loss of function of transcription factor EB remodels lipid metabolism and cell death pathways in the cardiomyocyte. Trivedi PC, Bartlett JJ, Mercer A, Slade L, Surette M, Ballabio A, Flibotte S, Hussein B, Rodrigues B, Kienesberger PC, Pulinilkunnil T. Biochim Biophys Acta Mol Basis Dis. 2020 May 8;1866(10):165832. doi: 10.1016/j.bbadis.2020.165832.

Glucolipotoxicity following nutrient overload causes cardiomyocyte injury by inhibiting TFEB and suppressing lysosomal function. We ascertained whether in addition to the amount, the type of fatty acids (FAs) and duration of FA exposure regulate TFEB action and dictate cardiomyocyte viability. Saturated FA, palmitate, but not polyunsaturated FAs decreased TFEB content in a concentration- and time-dependent manner in cardiomyocytes. Hearts from high-fat high-sucrose diet-fed mice exhibited a temporal decline in nuclear TFEB content with marked elevation of diacylglycerol and triacylglycerol, suggesting that lipid deposition and TFEB loss are concomitant molecular events. Next, we examined the identity of signaling and metabolic pathways engaged by the loss of TFEB action in the cardiomyocyte. 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 macroautophagy, mitophagy and lysosome function constituted a small portion of DEGs in TFEB^-/- cardiomyocytes. In myoblasts and/or myocytes, nutrient overload-induced lipid droplet accumulation and caspase-3 activation were exacerbated by silencing TFEB or attenuated by overexpressing constitutively active TFEB. The effect of TFEB overexpression were persistent in the presence of Atg7 loss-of-function, signifying that the effect of TFEB in the myocyte is independent of changes in the macroautophagy pathway. In the cardiomyocyte, the non-canonical effect of TFEB to reprogram energy metabolism is more evident than the canonical action of TFEB on lysosomal autophagy. Loss of TFEB function perturbs metabolic pathways in the cardiomyocyte and renders the heart prematurely susceptible to nutrient overload-induced injury. Read here