Cardiac Sirt1 Has a Protective Role in Lipotoxic Cardiomyopathy through Maintaining Membrane Fatty Acid Composition

Backgrounds: Lipotoxicity causes cardiac dysfunction in diabetes and obese. One potential mechanism is the effects of membrane fatty acid composition. Sirt1 is activated by exercise and calorie restriction, both of which have proved to be effective for lipotoxicity. We investigated a role of Sirt1 in the homeostasis of membrane fatty acid composition and cardiac function in lipotoxic cardiomyopathy. Methods and Results: (1) In neonatal rat cardiomyocytes, cell death induced by palmitate, a saturated fatty acid, was exacerbated in Sirt1-knockdown (Sirt1 KD) and was ameliorated by Sirt1 activator (nicotinamide mononucleotide). (2) Palmitate-overload changed membrane fatty acid composition; it increased palmitate and decreased oleate, a monounsaturated fatty acid. Such a change in membrane fatty acid composition was exaggerated in Sirt1 KD. (3) The expression of stearoyl-CoA desaturase 1 (SCD1), which converts saturated fatty acid to monounsaturated fatty acid, was increased by palmitate. This SCD1 induction was not observed in Sirt1 KD. (4) SCD1 overexpression could rescue both palmitate-induced membrane fatty acid composition change and cell death in Sirt1 KD. (5) Cardiomyocyte-specific Sirt1-knockout mice fed a high fat diet showed more severe diastolic dysfunction with an increase in cardiomyocyte death, fibrosis, and hypertrophy compared with control mice. Conclusions: Cardiac Sirt1 confers resistance against lipotoxic cardiomyopathy by preventing an increase in membrane saturated fatty acid content via the induction of SCD1.