Human apolipoproptein A-I: Structure, function and patogenicity

Team of work

Principal InvestigatorGonzalez-Marina

González, Marina Cecilia

Investigator
marinacego@hotmail.com

Díaz Lodovico, IvoDíaz Ivo

Research Fellow
diazludovico@med.unlp.edu.ar

Tarraga, WilsonTarraga

Research Fellow
wilson14_17@hotmail.com

Collaborators from other institutions

Gratton, Enrico
Laboratorio de Dinámica de fluorescencia. Universidad de California en Irvine. USA.

Lamy, María T.
Departamento de Física. Universidad de Sao Paulo. Sao Paulo. Brasil.

Grasa, María del Mar
Universidad Autónoma de Barcelona (UB). España.

Esteve, Montserrat
Universidad Autónoma de Barcelona (UB). España.

Mendoza, Aminta
Departamento de Física. Universidad Nacional de Colombia. Bogotá. Colombia.

Soulages, José Luis
Departamento de Bioquímica y Biología Molecular. Oklahoma. Universidad Estatal. USA.

Gennaro, Ana María
Departamento de Física. Universidad Nacional del Litoral. Santa Fé. Argentina.

Line overview

Biochemistry and Biophysics of High-density lipoproteins (HDLs) apolipoprotein A-I

The apolipoprotein A-I (apoAI) is the major protein of high density lipoproteins (HDL) which serum levels are inversely related to atherogenic risk.
Antiatherogenicity of apoAI and HDL may be attributed to their participation in the transport of excess cholesterol from peripheral tissues to liver for its catabolism and excretion, as well as their capacity to neutralize endotoxins and to inhibit the inflammatory response.
In order to know the molecular mechanisms involved in this process, the structure-function-pathogenicity relationship of apoAI should be studied in the context of the following sublines:

• Conformational flexibility of ApoAI.

Important conformational changes are necessary for the apoAI to alternate its functional cycle, either free or bound to lipid surfaces such as membranes or different HDL complexes. In its free state it presents a loose and flexible bunch of amphipatic helices which opens for the interaction of lipid surfaces. The goal of this work is to get insight into the structural basis of the apoAI interaction with lipids and conformational flexibility. In particular, we are interested in investigating a central protein region that would be involved in a structural, functional domain which would be responsible for the interaction of apoAI and discoidal HDL with membranes as well as for some cellular responses as the mobilization of endogenous stores of cholesterol. Different biophysical procedures have been used, either wild protein or with mutants at certain positions (trytophan or cysteine which are covalently bound to fluorescent or paramagnetic groups). These modified proteins are essential to know the reporting group, and estimate inter- or intra molecular distances that can reveal the spatial conformation. Also, a strategy to utilize computer methods for modeling and molecular dynamics has been designed.

• Metabolism and cholesterol transport in the first stages of reverse transport.

Depending on the cell type, apoAI is able to trigger multiple responses, though mechanisms and involved signaling pathways are still poorly known. For the last years we have paid special attention to one of those responses that is the endogenous store mobilization of esterified cholesterol. Not only the identification of signaling pathways but also the functional domains involved in these cell responses are crucial to understand those processes at a molecular level.
Different types of culture cells are utilized for investigating cell responses to apoAI, different types of HDL complexes, and artificial or natural mutants of apoAI. Thus, we try to gather information on the apoAI conformation and the involved protein domains. Currently, a natural mutant with a deletion at the central region (DK107) which carriers have an increased atherogenic risk is being investigated.

Inflammatory response mediated by Low Density Lipoproteins (LDLs) and glucocorticoids

Atherosclerosis is a pathology that involves an underlying inflammatory state which influences the progression of the disease. The pathology implies the synthesis of a great number of pro- and anti-inflammatory cytokines. Also the development of an atherosclerotic plaque starts with the recruitment and infiltration of circulating monocytes in areas of lipid deposition with physical damage in which “foams cells” macrophages or “foamy cells” are differentiated when endocyting altered lipoproteins such as oxidized low density lipoproteins (LDL-Ox) internalized in the arterial wall. Cortisol is a glucocorticoid with anti-inflammatory action that acts in the inflammatory resolution through, among other actions, the activation of the population of type M2c anti-inflammatory macrophages, inhibition of pro-inflammatory cytokines and inhibition of LDL-Ox-specific receptors (Toll like receptor type 4). The present line of work includes the study of molecular mechanisms involved in the endogenous anti-inflammatory response through glucocorticoids.

Effects of inhibitors with antiatherogenic implication on the activity of the lipid transfer protein (CETP).

The cholesteryl ester transfer protein (CETP) has an integral role in the metabolism of plasmatic lipoproteins. CETP facilitates the remodeling of high density proteins (HDL) in plasma because it promotes apoA-I interconversion contained in the spherical HDLs in “lipid- poor particles” and preβ-HDLs, as well as it exchanges cholesteryl esters among the different subparticles of HDLs, activity named homotypic. Also CETP is involved in ester cholesterol (EC) transference from HDLs to low density and very low density lipoproteins (LDL and VLDL) and in the transference of triglycerides (TG) from VLDL/LDL to HDLs, activity named heterotypic. In this way, CETP favors the increase of cholesterol content in LDL with the subsequent propensity to the development of the atherogenic plaque. CETP heterotypic inhibition could be effective to reduce atherosclerosis by a mechanism dependent on the cholesterol reduction of VLDL-LDL and its increase in HDLs. The use of “in-silico” tools of molecular docking and virtual sieving are usually effective for the search of inhibitors.
The present line of research also includes biochemical testing methodology of inhibitors in macrophage cellular lines. CETP pharmacological inhibition could lead to a cardiovascular risk reduction what constitutes a current strategy of interest in the field of cardiovascular medicine.


Understanding the role of apolipoproteinA-I in atherosclerosis. Post-translational modifications synergize dysfunction?.
Ludovico, Ivo Díaz; Gisonno, Romina A.; González, Marina C.; Garda, Horacio A.; Ramella, Nahuel A.; Tricerri, M. Alejandra.
2021. Biochimica et biophysica acta-general subjects. : ELSEVIER SCIENCE BV - . vol. 1865, n° 1, ISSN 0304-4165

Analysis of pyrene-labelled apolipoprotein A-I oligomerization in solution: Spectra deconvolution and changes in P-value and excimer formation.
Tárraga, Wilson A.; Falomir-Lockhart, Lisandro J.; Garda, Horacio A.; González, Marina C.
2021. Archives of biochemistry and biophysics: ELSEVIER SCIENCE INC,- . vol. 699, ISSN 0003-9861

Macrophage apoptosis using alendronate in targeted nanoarchaeosomes.
Jerez, Horacio Emanuel; Altube, Maria J.; Gandola, Y; Gonzalez, L; Gonzalez, Mc; Morilla, Mj; Romero, El.
2021. European journal of pharmaceutics and biopharmaceutics. , Amsterdam: ELSEVIER SCIENCE BV, - .p. 42-54. ISSN 0939-6411

Apoptotic cell death induced by dendritic derivatives of aminolevulinic acid in endothelial and foam cells co-cultures.
Céspedes, Mariela A.; Saénz, Daniel A.; Calvo, Gustavo H.; González, Marina; Macrobert, Alexander J.; Battah, Sinan; Casas, Adriana G.; Di Venosa, Gabriela M.
2021. Photochemical and photobiological sciences: ROYAL SOC CHEMISTRY,- . vol. 20, n° 4, p. 489-499. ISSN 1474-905X

Dataset on pyrene-labelled apolipoprotein A-I, model development and fitting to monitor oligomeric species of its lipid-free form.
Tarraga W; Garda H. A; Falomir Lockhart L; Gonzalez M. C.
2021. Data in brief: Elsevier, 2021 - . vol. 13, n° 35, ISSN 2352-3409

Dataset of the construction and characterization of stable biological nanoparticles.
Gisonno, Romina A.; Tricerri, M. Alejandra; González, Marina C.; Garda, Horacio A.; Ramella, Nahuel A.; Díaz Ludovico, Ivo.
2020. Data in brief. Amsterdam: Elsevier Inc., vol. 33, ISSN 2352-3409
doi.org/10.1016/j.dib.2020.106536

Metodologías para la detección de SARS-CoV-2 y análisis de carga viral mediante RT-PCR cuantitativa.
Jaquenod De Giusti, Carolina; Montanaro, Mauro; Mencucci, Maria Victoria; Canzoneri, Romina; Orlowski, Alejandro; Santana, Marianela; Pereyra, Erica; Kraemer, Mauricio Horacio; Pedríni, Nicolás; González Baro, María; Vila Petroff, Martin; Aiello, Alejandro; Abba, Martin; Lavarías, Sabrina María Luisa; Moscoso, Verónica; Costantini, Noelian; Francini, Flavio; Garda, H.
2020. Innovación y desarrollo tecnológico y social (idts). La Plata: Universidad Nacional de La Plata. vol. 2, n° 2, p. 1-14
doi.org/10.24215/26838559e013

Triacylglycerol synthesis directed by glycerol-3-phosphate acyltransferases -3 and -4 is required for lipid droplet formation and the modulation of the inflammatory response during macrophage to foam cell transition.
Quiroga, Ivana Y.; Pellon-Maison, Magali; González, Marina C.; Coleman, Rosalind A.; González Baro, Maria R.
2020. Atherosclerosis. ELSEVIER IRELAND LTD. ISSN 0021-9150
doi.org/10.1016/j.atherosclerosis.2020.11.022

Potential Inhibitors of the Activity of the Cholesterol-Ester Transfer Protein.
Tárraga, Wilson Alberto; Garda, Horacio Alberto; Toledo, Juan Domingo; González, Marina Cecilia.
2019: Journal of computational biology. New York: Mary Ann Liebert, Inc., vol. 26, n° 12, p. 1458-1469.
doi.org/10.1089/cmb.2018.0227

Role of cortisol in inflammationtriggered by macrophages exposition to modified LDL.
Toledo, J. D; Montserrat, E; Grasa, M. Del M; Ledda, A; Garda, H. A; Gulfo, J; Díaz, L. I; Ramella, N; Gonzalez, M. C.
2016. Data in brief-journal: Elsevier, vol. 8, p. 251-257

Data related to inflammation and cholesterol deposition triggered by macrophages exposition to modified LDL.
Toledo, J. D; Rafols, M; Grasa, M; Ledda, A; Garda, H. A; Gulfo, J; Diaz, L. I; Ramella, N; Gonzalez, M. C.
2016. Data in brief: Elsevier, vol. 8, p. 251-257

Decreased OxLDL uptake and cholesterol efflux in THP1cells elicited by cortisol and by cortisone through 11b-hydroxysteroid dehydrogenase type 1.
Ledda, A; Gonzalez. M; Gulfo, J; Díaz, L. I; Ramella, N; Toledo, J; Garda, H; Grasa, M; Montserrat, E.
2016. Atherosclerosis. Amsterdam: ELSEVIER IRELAND LTD, vol. 250, p. 84-94. ISSN 0021-9150

Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease.
Rodriguez, L; Vallecorsa, P; Battah, S; Di Venosa, G; Calvo, G; Mamone, L; Saenz, D; Gonzalez, M. C; Batlle, A; Macrobert, A. J; Casas, A.
2015. Photochemical and Photobiological Sciences. CAMBRIDGE: ROYAL SOC CHEMISTRY. vol. 14, n° 9, p. 1617-1627. ISSN 1474-905X

Apolipoprotein A-I configuration and cell cholesterol efflux activity of discoidal lipoproteins depend on the reconstitution process.
Cuellar, L. A; Prieto, E; Cabaleiro, L; Garda, H. A.
2014. Biochimica et Biophysica acta-molecular and cell biology of lipids. Amsterdam: ELSEVIER SCIENCE BV,. vol. 1841, p. 180-189. ISSN 1388-1981

Apolipoprotein A-I Helsinki promotes intracellular acyl-CoA cholesterol acyltransferase (ACAT) protein accumulation.
Toledo, J. D; Garda, H. A; Cabaleiro, L. V; Cuellar, A; Pellón Maison, M; González Baró, M; Gonzalez M. C.
2013. Molecular and cellular biochemistry. New York: SPRINGER. vol. 377, n° 1-2, p. 197-205. ISSN 0300-8177

Apolipoproteína A-I y lipoproteínas de alta densidad: Estructura y rol en la homeostasis del colesterol celular.
Garda, H. A; Toledo, J. D; González, M. C; Prieto, E; Cuellar, L. A; Cabaleiro, L. V; Chirillano, L. A; Almeyra, C. M.
2013. Acta Bioquímica Clínica Latinoamericana. La Plata: Federacion Bioquímica Provincia Buenos Aires, vol. 47, n° 2, p. 327-341. ISSN 0325-2957

El Dr. Rodolfo R. Brennner y una de sus principales obras: El Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP).
Garda, H. A.
2013. La Plata. Acta Bioquímica Clínica Latinoamericana. Federacion Bioquímica Provincia Buenos Aires. vol. 47, n° 2, p. 249-266. ISSN 0325-2957

Characterization of a human apolipoprotein A-I construct expressed in a bacterial system.
Prieto, E. D; Ramella, N; Cuellar, L. A; Tricerri, M. A; Garda, H. A.
2012. Protein journal. Berlin: Springer, vol. 31, n° 8, p. 681-688

Effect of reconstituted discoidal high density lipoproteins on lipid mobilization in RAW 264.7 and CHOK1 cells.
Toledo, J. D; Cabaleiro, L. V; Garda, H. A; González, M. C.
2012. Journal of cellular biochemistry. New York: Wiley-Liss, Div John Wiley & Sons Inc. vol. 113, n° 4, p. 1208-1216

Membrane insertion topology of the central apolipoprotein A-I region. Fluorescence studies using single tryptophan mutants.
Prieto, E. D; Garda, H. A.
2011. Biochemistry 50, 466 - 79. Editorial: American Chemical Society.

Human Apolipoprotein A-I-Derived Amyloid: it’s Association with Atherosclerosis.
Ramella, N. A; Rimoldi, O. J; Prieto, E. D; Schinella, G. R; Sanchez, S. A; Jaureguiberry, M.S; Vela, M.E; Ferreira, S. T; Tricerri, M. A.
2011. PLoS One. 2011 ;6 (7): e22532. Epub 2011 Jul 19

Structure and stability of crustacean lipovitellin: Influence of lipid content and composition.
García, C. F; Cunningham, M; Soulages, J. L; Heras, H; Garda, H. A.
2010. Comparative biochemistry and physiology. part b, biochemistry & molecular biology. Elsevier Science Inc. vol. 155, n° 2, p. 126 - 131

Membrane Organization and Regulation of Cellular Cholesterol.
Jaureguiberry, M. S; Tricerri, M. A; Sanchez, S. A; Garda, H. A; Finarelli, G. S; Gonzalez, M. C; Rimoldi. O. J.
2010. Journal of membrane biology. New York: Springer. vol. 234, p. 183 - 194

The central type Y amphipathic ahelices of apolipoprotein AI are involved in the mobilization of intracellular cholesterol depots.
González, M. C; Toledo, J. D; Tricerri, M. A; Garda, H. A.
2008. Archives of biochemistry and biophysics. Amsterdam: Elsevier, vol. 473, n° 1, p. 34 - 41

Embryo lipoproteins and yolk lipovitellin consumption during embryogenesis in Macrobrachium borellii (Crustacea: Palaemonidae).
García, C. F; Cunningham, M; Garda, H. A; Heras, H.
2008. Comparative biochemistry and physiology. part b, biochemistry & molecular biology, vol. 151, p. 317 - 322

Distinción “2020 Paul Dudley White International Scholar”
The American Heart Association presents this “Paul Dudley White International Scholar Award”
To Recognize the Authors with the Highest Ranked Abstract from Argentina Vascular Discovery: From Genes to Medicine Scientific Sessions 2020.Ivo Díaz Ludovico, Shimpi Bedi, John T. Melchior, Marina González, Horacio Garda, Sean Davidson.

“Premio SAB al mejor trabajo”
III Congreso Iberoamericano de Biofísica y XXVI Reunión Anual de la Sociedad Argentina de Biofísica. Buenos Aires. Septiembre de 1997
Conformation of apolipoprotein A-I in reconstituted lipoprotein particles and particle-membrane interaction. Effect of size and cholesterol.
Tricerri, M. A; Córsico, B; Toledo, J. D; Garda, H. A; Brenner, R. R.

“Premio SAB al mejor trabajo”
XXXI Reunión Anual de SAB. Buenos Aires. Diciembre de 2002
Interacción del dominio central de apolipoproteína A-I con membranas.
Prieto, E. D; Toledo, J. D; Garda, H. A.

“Mención de honor”
IV Congresso de Biofísica do Cone-Sul XXIX Reunión Anual de SAB. Campinas, SP, Brazil. Agosto de 2000
Trabajo: Interacción de complejos lipoproteicos discoidales de apolipoproteína A-I con vesículas lipídicas estudiada con reactivos fotoactivables.
Córsico, B; Toledo, J. D; Garda, H. A.

“Mejor poster de ciencias básicas”
Otorgado en Jornadas de la Facultad de Ciencias Médicas. La Plata. Octubre de 2010. Correspondiente al trabajo:
Configuración de la apolipoproteína A-I ( LL5/2 en dHDL) fisiológicamente activa en la remoción de colesterol de células RAW.
Cuellar, L. A; Prieto, E. D; Cabaleiro, L. V; González, M. C; Garda, H. A.




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