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Doctoral Thesis
DOI
10.11606/T.42.2014.tde-19022015-160342
Document
Author
Full name
Juan Pablo Zúñiga Hertz
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2014
Supervisor
Committee
Abdulkader, Fernando Rodrigues de Moraes (President)
Miranda Filho, Manoel de Arcisio
Passarelli, Marisa
Rodrigues, Alice Cristina
Rossoni, Luciana Venturini
Title in Portuguese
Influência do colesterol e de intermediários da sua biossíntese sobre a maquinaria de secreção de insulina e a organização funcional da membrana plasmática em células secretoras de insulina.
Keywords in Portuguese
Colesterol
Insulina
Isoprenila
Membrana
Secreção
Abstract in Portuguese
A rota de biossíntese de colesterol tem sido estudada pelo seu envolvimento com a secreção de hormônios. A secreção de insulina depende do colesterol e de intermediários da sua biossíntese como o geranilgeranil pirofosfato. Para compreender a contribuição destes elementos na secreção de insulina foram utilizados inibidores de diferentes pontos da rota de biossíntese do colesterol. Estudou-se a contribuição do geranilgeranil pirofosfato e do colesterol na secreção de insulina estimulada pela glicose e analisados parâmetros físicos de membrana dos quais decorrem aspectos funcionais da célula beta. Sinvastatina inibiu a secreção de insulina sem afetar o conteúdo celular de colesterol, mas inibindo a geranilgeranilação de proteínas. A diminuição do conteúdo de colesterol aumenta a fluidez de membrana desorganizando lipid rafts. A suplementação com colesterol recupera a função secretória. Por tanto, a inibição da síntese de colesterol diminui a secreção de insulina através da redução da isoprenilação de proteínas e da alteração estrutural de membranas celulares.
Title in English
Influence of cholesterol and its biosynthesis intermediates on the insulin secretion machinery and the functional organization of the plasma membrane in insulin secreting cells.
Keywords in English
Cholesterol
Insulin
Isoprenyl
Membrane
Secretion
Abstract in English
Cholesterol biosynthesis pathway has been studied for its involvement with the hormone secretion process. Insulin secretion depends on cholesterol and its biosynthesis intermediates such as geranylgeranyl pyrophosphate. For understand their contribution on the glucose stimulated insulin secretion, cholesterol biosynthesis pathway key steps inhibitors were used. The geranylgeranyl pyrophosphate and cholesterol contribution to the insulin secretion was studied so as physical parameters of the membrane, from where derive key functions of it. Simvastatin inhibited insulin secretion without affecting total cellular cholesterol, but inhibiting protein geranylgeranylation. The cholesterol reduction increased the membrane fluidity with consequent disorganization of membrane lipid rafts, in which secretion machinery is organized. Cholesterol supplementation recovers cellular secretory function. We conclude that cholesterol biosynthesis inhibition reduces insulin secretion through protein isoprenylation impairment and structural disarrangement of the cellular membranes.
 
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Release Date
2017-02-19
Publishing Date
2015-02-20
 
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