Background: It has been proposed that curcumin modulates the gene expression of different signaling pathways, improve the fatty acids metabolism and exerts a potential beneficial effect on cardiometabolic disease, but this has not been thoroughly demonstrated. In the present study, we evaluated the effect of curcumin upon the expression of PPARα, CPT1, MCAD, VLCAD and ACAA2 in heart of mice fed a high-fructose diet (HFD).Methods: Twenty-four mice C57BL/6 were divided into four groups (n=6) and treated for 15 weeks. Control group (C) received standard diet (SD), Curcumin group (C+Cur), Fructose group (F) and Fructose with Curcumin group (F+Cur). The groups were treated with 0.75% w/w curcumin mixed in the SD and 30% w/v fructose in water, respectively. Heart proteins expression were analyzed by Western Blot.Results: Curcumin supplementation increased PPARα and ACAA2 expression and decreased CPT1 and MCAD expression in heart of mice fed a HFD. However, it did not modify the VLCAD expression.Conclusions: Curcumin regulated PPARα, CPT1 and MCAD expression and increased ACAA2 expression; suggesting a therapeutic potential in the prevention of alterations in mitochondrial fatty acids metabolism in heart of mice fed a HFD.