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Fibrates and ezetimibe effect on the jejunum: correlation of proteomic, molecular and functional findings with the improvement of obesity-induced hyperlipidemia

Abstract

Fenofibrate (FF) and ezetimbe (EZ) treatments of dyslipidemia prevent cardiovascular diseases by decreasing serum cholesterol (TC) and triacylglycerols (TAG) levels. Despite of FF, a PPAR-a agonist, increases lipids oxidation and EZ inhibits intestinal cholesterol uptake, it is not clear whether lipids absorption reduce after FF and EZ administration, which would directly impact the lipemic profile. Our hypothesis is that FF and EZ promote morphological and functional alteration in the enterocytes, leading to decrease of metabolism and content of the TC and TAG secreted into lymph, which could improve the dyslipidemia. To confirm our hypothesis, C57BL/6 male mice will be fed a normal diet or high-fat diet (HFD) during nine weeks followed by 15 days of FF and EZ treatment. Mice will be euthanized and the jejunum will be removed for the following assessments: a) morphology by electron microscopy; b) paracellular permeability; c) TC and TAG absorption and reesterification; d) and proteomics and phosphoproteomics analysis. The blood will be collected for lipids measurement (TC, TAG, LDL-C, HDL-C). TLR4 KO mice will be used to evaluate TLR4 signaling pathway after HFD feeding and FF and EZ treatment. The results will allow us to associate morphofunctional and proteomic findings in the jejunum with the improvement of dyslipidemia, that means, describing a robust mechanism of action for FF and EZ as well as identify their targets in the intestine, which will contribute for understanding the physiology and pharmacology of dyslipidemia. (AU)

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