Role of SIRT6 in the Regulation of Glucose Metabolism and Fatty Acid Uptake in Heart

Abstract

The adult heart heavily relies on fatty acid for most of its energy supplies. The heart derives most of the fatty acid from circulation. Hence, fatty acid uptake forms a crucial step in cardiac metabolism. Studies have shown that fatty acid transporters are upregulated during cardiac metabolic syndrome. This results in the accumulation of lipids in the heart leading to cardiac lipotoxicity. To test the role of SIRT6 in fatty acid uptake in the heart, we examined SIRT6 levels in diabetic mice models. Our analysis suggested that SIRT6 was downregulated in the heart of diabetic mice. In addition to this, there was a concomitant increase in the expression of fatty acid transporters in the heart of diabetic mice. In line with these results, an increase in fatty acid uptake in the SIRT6 depleted cardiomyocytes. Moreover, SIRT6 depleted cardiomyocytes have increased lipid accumulation. In addition to this, SIRT6 overexpression significantly attenuated fatty acid uptake as well as fatty acid accumulation. Further, we found SIRT6 regulates fatty acid uptake irrespective of the cell type suggesting a global role. Interestingly, our results suggest that SIRT6 regulates fatty acid uptake independent of its catalytic activity. Both wild-type and catalytic mutants of SIRT6 attenuate fatty acid uptake, concomitantly downregulating the fatty acid transporters in cardiomyocytes. Previous studies indicate that most of the fatty acid transporters' expression is governed transcriptionally under the control of peroxisome proliferator-activated receptors (PPAR). In line with this, we found SIRT6 and PPARγ are interacting partners. Further, our molecular docking experiment suggested SIRT6 interacts with the DNA binding domain of PPARγ. Our chromatin immunoprecipitation experiment showed that SIRT6 binds to the promoters of fatty acid transporters. Mechanistically, SIRT6 haploinsufficiency increased PPARγ occupancy on the promoters of fatty acid transporters. Moreover, inhibiting PPARγ using pharmacological inhibitors significantly rescued both fatty acid uptake and fatty acid accumulation in the cardiomyocytes. Together, our findings reveal a novel role of SIRT6 in regulating cardiac fatty acid transport and lipotoxicity.