Exploration of a combination Phytosterol and Ezetimibe therapy for the treatment of combined dyslipidemia in a Syrian golden hamster model
Griffin, John D.
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Ezetimibe (EZ) and Phytosterols (PS) are the best-defined drug and nutraceutical approaches for lowering blood cholesterol. Furthermore, both EZ and PS appear to have triglyceride (TAG)-lowering properties through as of yet unknown effects on intestinal lipid metabolism. Our work sought to examine blood lipid responses and changes in the expression of intestinal lipid-related proteins from treatment with EZ, PS, or a PS/EZ combination in Syrian golden hamsters. Forty-eight (n=12) male hamsters were assigned to 4 groups for 6 weeks: (a) Atherogenic diet (ATH); (b) ATH + 2% PS; (c) ATH + 0.002% EZ; and (d) ATH + PS/EZ. Compared with the ATH diet, non-HDL-C and TAG were reduced ( p <0.05) in response to PS (88 and 64%), EZ (100 and 103%), and PS/EZ (99 and 101%), with no difference ( P >0.05) between the single vs. combined therapies. Cholesterol absorption was reduced ( p <0.05) in the PS (27%), EZ (37%), and PS/EZ (38%) groups compared with the ATH group. Intestinal NPC1L1 protein abundance was reduced in the EZ group (1.44, p <0.05) while SREBP1c mRNA expression was reduced in the PS and PS/EZ groups (2.19 fold and 2.02 fold respectively, p <0.05). These results suggest that PS and EZ are effective treatments for combined dyslipidemia but no additional benefits are gained from a combined therapy. Additionally, our results reveal the possible mechanism whereby EZ and PS differentially modify intestinal CHOL absorption and serum TAG. We conclude that EZ exerts its effects through reductions in NPC1L1 while PS acts by reducing SREBP1c mRNA expression.