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Studies on the mechanisms involved in lipid body formation induced by a snake venom phospholipase A2 in isolated macrophages: participation of lipid homeosthasis factors

Grant number: 11/21341-5
Support Opportunities:Regular Research Grants
Duration: March 01, 2012 - January 31, 2015
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal Investigator:Catarina de Fatima Pereira Teixeira
Grantee:Catarina de Fatima Pereira Teixeira
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


Bothrops genus snake venoms contain high amounts of secretory phospholipases A2 (sFLA2) with high grade of structural and functional homology with mammalian sFLA2, which are increased in inflammatory diseases, such as atherosclerosis. We have recently shown that MT-III, a group IIA venom sFLA2 is able to directly induce lipid body formation and ADRP expression in macrophages. ADRP is a key protein in neutral lipid storage and lipid body biogenesis, and has been associated with foam cell formation. However, the mechanisms involved in these MT-III-induced effects were not elucidated, mainly those related to up-regulation of ADRP expression and accumulation of lipids into lipid bodies. In this study the knowledge of the mechanisms by which MT-III stimulates LB formation and ADRP expression in macrophages will be extended by focusing on major factors involved in lipid homeostasis. To this purpose, the effects of MT-III will be analyzed in macrophages with regard to: 1) gene and protein expression of the enzymes acyl-CoA:diacylglycerol acyltransferase (DGAT) and Acyl-CoA:cholesterol acyltransferase (ACAT), responsible for triacylglycerol and cholesterol, respectively; 2) levels of triacylglycerol and cholesterol; 3) activation and gene and protein expression of the receptors PPAR-delta and PPAR-beta/delta; 4) gene and protein expression of the CD36 receptor; 5) gene and protein expression of SREBP-2; 6) participation of the signaling proteins PKC, PI3K, PTK, JNK, p38MAPK, ERK1/2 and intracellular phospholipases A2 (cFLA2 and iFLA2) in MT-III- induced ADRP expression. In addition, participation of PPAR-gama, PPAR-beta/delta, CD36, DGAT and ACAT in both lipid body formation and up-regulation of ADRP expression induced by MT-III will be evaluated. This study will contribute to understanding the effects of both MT-III and sPLA2s in processes associated with lipid storage in immunocompetent cells, such as macrophages, as well as to a better knowledge of physiopathology of the local reaction induced by Bothrops venoms. Moreover, new therapeutic targets of lipid disorder-associated diseases may be identified. (AU)

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Scientific publications (5)
(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)
GIANNOTTI, KARINA CRISTINA; LEIGUEZ, ELBIO; MOREIRA, VANESSA; NASCIMENTO, NEIDE GALVAO; LOMONTE, BRUNO; MARIA GUTIERREZ, JOSE; DE MELO, ROBSON LOPES; TEIXEIRA, CATARINA. A Lys49 Phospholipase A(2), Isolated from Bothrops asper Snake Venom, Induces Lipid Droplet Formation in Macrophages Which Depends on Distinct Signaling Pathways and the C-Terminal Region. BIOMED RESEARCH INTERNATIONAL, . (11/21341-5, 07/03337-5, 10/06345-1)
MOREIRA, VANESSA; TEIXEIRA, CATARINA; DA SILVA, HENRIQUE BORGES; D'IMPERIO LIMA, MARIA REGINA; DOS-SANTOS, MARIA CRISTINA. The role of TLR2 in the acute inflammatory response induced by Bothrops atrox snake venom. Toxicon, v. 118, p. 121-128, . (11/21341-5, 14/00810-5, 13/07140-2)
LEIGUEZ, ELBIO; GIANNOTTI, KARINA CRISTINA; MOREIRA, VANESSA; MATSUBARA, MARCIO HIDEKI; MARIA GUTIERREZ, JOSE; LOMONTE, BRUNO; PABLO RODRIGUEZ, JUAN; BALSINDE, JESUS; TEIXEIRA, CATARINA. Critical Role of TLR2 and MyD88 for Functional Response of Macrophages to a Group IIA-Secreted Phospholipase A(2) from Snake Venom. PLoS One, v. 9, n. 4, . (11/21341-5, 10/06345-1)
LEIGUEZ, ELBIO; GIANNOTTI, KARMA CRISTINA; VIANA, MARIANA DO NASCIMENTO; MATSUBARA, MARCIO HIDEKI; FERNANDES, CRISTINA MARIA; GUTIERREZ, JOSE MARIA; LOMONTE, BRUNO; TEIXEIRA, CATARINA. A Snake Venom-Secreted Phospholipase A(2) Induces Foam Cell Formation Depending on the Activation of Factors Involved in Lipid Homeostasis. Mediators of Inflammation, . (11/21341-5, 15/24701-3, 14/18549-1, 13/22610-5, 10/08506-2, 10/06345-1)
GIANNOTTI, KARINA CRISTINA; LEIGUEZ, ELBIO; ZULIM DE CARVALHO, ANA EDUARDA; NASCIMENTO, NEIDE GALVAO; MATSUBARA, MARCIO HIDEKI; FORTES-DIAS, CONSUELO LATORRE; MOREIRA, VANESSA; TEIXEIRA, CATARINA. A snake venom group IIA PLA2 with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ(2) in macrophages. SCIENTIFIC REPORTS, v. 7, . (11/21341-5, 13/22610-5, 08/57898-0)

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