SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPAR gamma on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPAR gamma is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.

Automated summary

Pathological lipid accumulation in cardiomyocytes is associated with enhanced fatty acid uptake through specific transporters, regulated by the transcription factor SIRT6. SIRT6 deficiency leads to increased expression of fatty acid transporters and lipid accumulation, with its interaction with PPARγ being critical in regulating transporter expression.്