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Abstract
Energy substrate imbalance is a major cause of cardiac dysfunction. Vitamin D/vitamin D receptor (VD/VDR) deficiency is involved in the pathogenesis of various cardiac diseases; however, the exact underlying mechanism remains unclear. The aim of this study was to investigate whether vitamin D modulates mitochondrial fatty acid oxidase via sirtuin 3 signaling to protect the myocardium. 1-Alpha-hydroxylase-defficient mice exhibited a high metabolic rate and lower myocardial contractility than wild-type mice. Sirtuin 3 upregulation was detected in high-fat diet-fed mice receiving vitamin D3 compared with that in high-fat diet-fed mice. Both sirtuin 3 blockade and knockout inhibited the VD/VDR-induced downregulation of fatty acid oxidase in myocardial mitochondria. VD/VDR suppressed fatty acid metabolism by upregulating sirtuin 3 and lowering mitochondrial fat uptake, thereby improving myocardial function and balancing energy substrates, rather than by altering fat endocytosis and exocytosis.
Highlights
Cardiomyocyte energy metabolism encompasses the processes of substrate absorption, distribution, and utilization
1,25(OH)2D3 Protect Myocardial Function promoted the binding of vitamin D receptor (VDR) to the SIRT3 vitamin D response elements (VDREs) in HL-1 cardiac myocyte cells (Figures 7B,C). These results suggested that Vitamin D (VD) increased the expression of Sirt3 through VDR binding at the VDRE within the Sirt3 promoter
Previous works have suggested a role for VDR in the regulation of energy metabolism in vivo (Cianferotti and Demay, 2007; Nimitphong et al, 2012)
Summary
Cardiomyocyte energy metabolism encompasses the processes of substrate absorption, distribution, and utilization. There are three main energy substrate sources in heart cells, namely glycolysis (10– 20%), lactic acid (10–20%), and fatty acid oxidation (60–90%) (van Bilsen, 2004). Together, these maintain a relatively constant substrate availability in order to meet the organ’s energy demands. The imbalance of energy substrates, especially the excess of fatty acids, leads to the initiation of the pathological processes in cardiac tissue, including myocardial hypertrophy and myocardial necrosis (Fillmore et al, 2014; Fukushima and Lopaschuk, 2016). Myocardial function is known to be affected by hyperlipidemia, cardiac hypertrophy, coronary atherosclerosis, and other conditions, the detailed mechanisms underlying their effects remain unclear
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