New insight into the cholesterol-lowering effect of phytosterols in rat cardiomyocytes

The exact mechanisms for cholesterol-lowering effect of phytosterols (PS) are not well defined yet. Dietary cholesterol minimally affects blood cholesterol, and regulation of cholesterolaemia could not exclusively rely on modification in intestinal absorption. Activation of sterol regulatory element-binding proteins (SREBPs), master regulators of lipid homeostasis, is tightly regulated through a sterol-sensing domain (SSD); in cholesterol-depleted cells, SREBP activation upregulates the expression of genes involved in cholesterol synthesis and trafficking. Since PS structure is very similar to cholesterol, they could be sensed by SSD, so preventing SREBP cleavage. To verify this hypothesis primary cultures of rat cardiomyocytes were supplemented with PS (sitosterol, campesterol, and brassicasterol, separately or in a mixture), cholesterol or mevastatin. PS were actively incorporated by cardiac cells, and caused a significant decrease in cholesterol cellular content. Genes encoding for SREBP2, HMGCR and LDLR were upregulated in cells treated with mevastatin, while no increase in their transcription was detected in PS-supplemented cardiomyocytes, although the reduction of cholesterol was similar in PS- and mevastatin-treated cells. According to herein reported data, it is conceivable that PS are sensed by the SSD so preventing the activation of the nuclear receptors and consequent upregulation of genes connected with cholesterol metabolism.