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Glycemic control and the removal of macrophage cholesterol by ABCA-1: role of modified albumin by advanced glycation

Grant number: 12/12088-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): October 01, 2012
Effective date (End): December 25, 2016
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marisa Passarelli
Grantee:Rodrigo Tallada Iborra
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/04831-1 - New players in glycemic control and chronic complications of Diabetes mellitus: preventive and therapeutic perspectives, AP.TEM
Associated scholarship(s):13/26256-1 - Intracellular trafficking of HDL receptor - ABCA-1 - in macrophages treated with advanced glycated albumin: influence of glycemic control in reverse cholesterol transport, BE.EP.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, promotting 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 cholestrol 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 controle 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 (6)
(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)
PINTO, PAULA R.; DA SILVA, KAROLLINE S.; IBORRA, RODRIGO T.; OKUDA, LIGIA S.; GOMES-KJERULF, DIEGO; FERREIRA, GUILHERME S.; MACHADO-LIMA, ADRIANA; ROCCO, DEBORA D. F. M.; NAKANDAKARE, EDNA R.; MACHADO, UBIRATAN F.; et al. Exercise Training Favorably Modulates Gene and Protein Expression That Regulate Arterial Cholesterol Content in CETP Transgenic Mice. FRONTIERS IN PHYSIOLOGY, v. 9, . (12/19112-0, 16/15603-0, 13/11084-0, 12/12088-7, 11/15153-1, 12/18724-2, 13/02854-7, 14/07617-6, 15/21072-5)
DA SILVA, KAROLLINE S.; PINTO, PAULA R.; FABRE, NELLY T.; GOMES, DIEGO J.; THIEME, KARINA; OKUDA, LIGIA S.; IBORRA, RODRIGO T.; FREITAS, VANESSA G.; SHIMIZU, MARIA H. M.; TEODORO, WALCY R.; et al. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats. FRONTIERS IN PHYSIOLOGY, v. 8, . (16/15603-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 14/17251-9, 13/02854-7)
MINANNI, CARLOS ANDRE; MACHADO-LIMA, ADRIANA; IBORRA, RODRIGO TALLADA; OKUDA, LIGIA SHIMABUKURO; PINTO, RAPHAEL DE SOUZA; MELLO SANTANA, MONIQUE DE FATIMA; DE ARAUJO LIRA, AECIO LOPES; NAKANDAKARE, EDNA REGINA; CARDILLO CORREA-GIANNELLA, MARIA LUCIA; PASSARELLI, MARISA. Persistent Effect of Advanced Glycated Albumin Driving Inflammation and Disturbances in Cholesterol Efflux in Macrophages. NUTRIENTS, v. 13, n. 10, . (17/18545-4, 12/19112-0, 16/15603-0, 12/12088-7, 18/00172-0, 15/21072-5)
PINTO, PAULA RAMOS; FERRARETTO MOURA ROCCO, DEBORA DIAS; OKUDA, LIGIA SHIMABUKURO; MACHADO-LIMA, ADRIANA; CASTILHO, GABRIELA; DA SILVA, KAROLLINE SANTANA; GOMES, DIEGO JUVENAL; PINTO, RAPHAEL DE SOUZA; IBORRA, RODRIGO TALLADA; FERREIRA, GUILHERME DA SILVA; et al. Aerobic exercise training enhances the in vivo cholesterol trafficking from macrophages to the liver independently of changes in the expression of genes involved in lipid flux in macrophages and aorta. LIPIDS IN HEALTH AND DISEASE, v. 14, . (12/19112-0, 11/04631-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 13/02854-7)
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)

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