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Intracellular trafficking of HDL receptor - ABCA-1 - in macrophages treated with advanced glycated albumin: influence of glycemic control in reverse cholesterol transport

Grant number: 13/26256-1
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): February 23, 2014
Effective date (End): May 22, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marisa Passarelli
Grantee:Rodrigo Tallada Iborra
Supervisor: Shinji Yokoyama
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Chubu University, Japan  
Associated to the scholarship:12/12088-7 - Glycemic control and the removal of macrophage cholesterol by ABCA-1: role of modified albumin by advanced glycation, BP.PD


In diabetes mellitus (DM), alterations in lipid and lipoprotein metabolism contribute to the elevated risk of atherosclerotic disease. Hyperglycemia is an important contributor for micro and macrovascular disease in DM, leading to the generation of reactive oxygen species (ROS) and the formation of reactive oxoaldehydes, such as glyoxal, methylglyoxal and glycolaldehyde that mediate the formation of advanced glycation end products (AGE). We recently demonstrated that AGE disturb the macrophage reverse cholesterol transport, promoting intracellular accumulation of total sterols (namely, cholesterol and 7-ketocholesterol) and oxidative and inflammatory stress. Advanced glycated albumin (AGE-albumin) reduces cellular ABCA-1 content independently of changes in its mRNA. In consequence, there is a diminished rate of cell cholesterol removal mediated by apo A-I leading to intracellular lipid accumulation. Elevated ROS generation and enhanced levels of endoplasmic reticulum stress markers (Grp 78 and Grp94) and unfolded protein response markers (eIF2-± and ATF6) relate to the reduction in ABCA-1 protein level. This is not ascribed to the endoplasmic reticulum associated degradation that is mediated by the ubiquitin proteasomal system, although lisossomal degradation (autophagy) and calpain-mediated surface degradation may contribute to the reduction of ABCA-1. In agreement to the results observed with in vitro glycated albumin, AGE-albumin isolated from poorly control DM patients serum adversely affects cholesterol removal and alters macrophage gene expression. Our hypothesis is that the adequate glycemic control may (HbA1c <7,0 % and fructosamine <300µmol/L ) revert the content of ABCA-1 and cholesterol efflux that is damaged in macrophages by AGE-albumin isolated during the poorly glycemic control. The benefit in ABCA-1 level on its turn may be determined by the modulation of degradation pathways, mainly mediated by calpain, ubiquitin proteasomal and lisossomal systems. The outcomes of this study will contribute to clarify the benefit of adequate glycemic control (reflected by the reduction of albumin glycation) on the prevention of ABCA-1 mediated cholesterol efflux disturbances. In other words, results will help to identify how glycemic control contributes to the prevention of lipid accumulation in macrophages, and then to atherosclerosis in DM. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
IBORRA, RODRIGO TALLADA; MACHADO-LIMA, ADRIANA; OKUDA, LIGIA SHIMABUKURO; PINTO, PAULA RAMOS; NAKANDAKARE, EDNA REGINA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA; PICKFORD, RUSSELL; WOODS, TOM; BRIMBLE, MARGARET A.; et al. AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages. JOURNAL OF DIABETES AND ITS COMPLICATIONS, v. 32, n. 1, p. 1-10, . (12/19112-0, 13/26256-1, 16/15603-0, 12/12088-7, 13/02854-7, 15/21072-5)
MACHADO-LIMA, ADRIANA; LOPEZ-DIEZ, RAQUEL; IBORRA, RODRIGO TALLADA; PINTO, RAPHAEL DE SOUZA; DAFFU, GURDIP; SHEN, XIAOPING; NAKANDAKARE, EDNA REGINA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA CARDILLO; SCHMIDT, ANN MARIE; et al. RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 19, . (12/19112-0, 15/21072-5, 13/06800-9, 18/00172-0, 13/26256-1, 12/12088-7, 14/05951-6, 16/15603-0)
OKUDA, LIGIA SHIMABUKURO; IBORRA, RODRIGO TALLADA; RAMOS, PAULA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA; PICKFORD, RUSSELL; WOODS, TOM; BRIMBLE, MARGARET ANNE; RYE, KERRY-ANNE; PASSARELLI, MARISA. Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages. Mediators of Inflammation, v. 2020, . (13/23392-1, 16/15603-0, 15/21072-5, 13/02854-7, 13/26256-1)

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