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The role of CETP (cholesterol ester transfer protein) on the uptake, cellular distribution and hepatic excretion of lipopolysaccharide

Grant number: 17/22940-6
Support type:Regular Research Grants
Duration: February 01, 2019 - January 31, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Patricia Miralda Cazita
Grantee:Patricia Miralda Cazita
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

CETP is a glycoprotein known to mediate the exchange the cholesteryl ester from high-density lipoprotein (HDL) to apoB-rich lipoproteins triglycerides. The CETP activity is inversely related to HDL-cholesterol (HDL-C). Recently, the increase in HDL-C levels by inhibition of CETP activity became a target of new drug developments. However, investigations utilizing CETP inhibitors have so far failed to provide protection against cardiovascular disease. The first inhibitor, Torcetrapib, was discontinued because was associated with increased the blood pressure, câncer, infection and total mortality, in spite of markedly increasing the plasma HDL concentration. In this regards, our studies show enhances the survival rate in mice expressing the human CETP gene after experimental sepsis than Wild type mice (WT). In addition, the reduction of plasma cytokines and hepatic Toll-like receptor 4 (TLR4) expression. Our hypothesis is, in the presence of CETP, the LPS in systemic circulation is more quickly removed, the liver uptake and released into the bile for excretion into the faeces. It is known that most of the free LPS is uptake by the Kupffer cells (KC), whereas the LPS associated with lipoproteins appears to be purified by the hepatocytes; the presence of CETP would facilitate the redirection of LPS from KC to the hepatocyte attenuating the host response to infection. The aim of this study is to investigate: 1) the role of CETP in the LPS transfer between KC and hepatocyte, the plasma clearance, tissue uptake and biliary excretion in mice that express CETP compared to WT; 2) to analyze macrophage subpopulations, the gene expression levels of receptors and proteins which is involved in lipids and LPS metabolism such as TLR4, SR-B1, ABCA-1, B-E, CETP and AOAH and the release of cytokines. We hope to contribute to the generation of relevant information about the physiology of sepsis and the development of new approaches. (AU)