Anti-inflammatory role of apolipoprotein A-IV in diabetes mellitus and its impact on macrophage reverse cholesterol transport: influence of advanced glycation

• Grant number: 13/02854-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): October 01, 2013
• Effective date (End): July 06, 2019
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marisa Passarelli
• Grantee: Ligia Shimabukuro Okuda
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 16/15603-0 - Unraveling mechanisms of glycemic control and chronic complications of Diabetes mellitus: contributions to human health, AP.TEM
• Associated scholarship(s): 13/23392-1 - Anti-inflammatory function of apolipoprotein A-IV in diabetes mellitus and its effects on reverse cholesterol transport from macrophages: influence of modification by advanced glycation, BE.EP.PD

Abstract

The inverse association between HDL and coronary heart disease is well established by epidemiological studies although recent clinical trials and genetic studies have failed in demonstrating cardiovascular benefits by increasing plasma HDL-cholesterol levels. This may be related to the great heterogeneity of HDL particle in size and composition and to the partial loss of function of this lipoprotein. Recently, HDL proteome has demonstrated a different profile of HDL proteins in cardiovascular disease, namely by a reduced concentration of apoA-IV. As apoA-I, apoA-IV presents anti-inflammatory properties and exerts antiatherogenic roles by different mechanisms. In diabetes mellitus, apoA-I modification by advanced glycation end products (AGE) changes its biological properties and its ability to inhibit inflammation and oxidation and to stimulate cholesterol efflux. We recently demonstrated that advanced glycation primes macrophages for inflammation elicited by calgranulins and lipopolysaccharide (LPS), impairing macrophage cholesterol efflux by diminishing the expression of the HDL receptor, ABCA1. In addition, in the presence of AGE, HDL is not able to prevent the secretion of inflammatory markers by macrophages. Our proposal is to analyze the anti-inflammatory property of apoA-IV in diabetes mellitus especially looking at the influence of advanced glycation and how this impacts macrophage reverse cholesterol transport. For this purpose, apoA-IV will be isolated from well and poorly controlled diabetes mellitus patients and healthy control subjects´ plasma. In addition, recombinant apoA-IV will be produced by E.coli and submitted to in vitro glycation. Mouse peritoneal macrophages and human coronary artery endothelial cells (HCAECs) will be treated with different types of apoA-IV and then exposed to LPS. The conditioned medium will be collected in order to measure the production of inflammatory cytokines and adhesion molecules and to treat naive macrophages previously overloaded with cholesterol and 14C-cholesterol to assess the apoA-I mediated cholesterol efflux. In cells, it will be determined: Inflammatory mediators and NF-kB mRNA and protein levels of HDL receptors (ABCA-1 and ABCG-1). Results will help to elucidate the antiatherogenic role of apo A-IV, how this is disturbed by advanced glycation in diabetes mellitus and how can be ameliorated by adequate glycemic control. (AU)

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)

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, JAN 2018. (12/19112-0, 13/26256-1, 16/15603-0, 12/12088-7, 13/02854-7, 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, SEP 16 2015. (12/19112-0, 11/04631-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 13/02854-7)

GOMES, DIEGO JUVENAL; VELOSA, ANA PAULA; OKUDA, LIGIA SHIMABUKURO; FUSCO, FERNANDA BUENO; DA SILVA, KAROLINNE SANTANA; PINTO, PAULA RAMOS; NAKANDAKARE, EDNA REGINA; CORREA-GIANNELLA, MARIA LUCIA; WOODS, TOM; BRIMBLE, MARGARET ANNE; et al. Glycated albumin induces lipid infiltration in mice aorta independently of DM and RAS local modulation by inducing lipid peroxidation and inflammation. JOURNAL OF DIABETES AND ITS COMPLICATIONS, v. 30, n. 8, p. 1614-1621, NOV-DEC 2016. (13/11084-0, 11/04631-0, 12/19755-9, 11/16164-7, 13/02854-7, 13/23392-1)

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, JAN 14 2020. (13/23392-1, 16/15603-0, 15/21072-5, 13/02854-7, 13/26256-1)

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, MAY 8 2018. (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, SEP 22 2017. (16/15603-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 14/17251-9, 13/02854-7)