Oleic acid increases the transcriptional activity of FoxO1 by promoting its nuclear translocation and ß-catenin binding in pancreatic ß-cells.
Biochim Biophys Acta Mol Basis Dis
; 1865(10): 2753-2764, 2019 10 01.
Article
em En
| MEDLINE
| ID: mdl-31255704
ABSTRACT
In the setting of metabolic overload, chronic elevations of free fatty acids in blood and tissues are associated with pancreatic ß-cell lipotoxicity and failure. Ultimately, obesity combined with insulin resistance increases the dysfunctional demand of ß-cells and contributes to the development of type 2 diabetes. Forkhead box O1 (FoxO1) is a potent transcriptional regulator of pancreatic ß-cell function and tolerance to lipid stress. The present study examined the effects of stearoyl-CoA desaturase 1 (SCD1)-metabolized precursors and products, notably oleic acid, on the compensatory capacity of ß-cells and their relationship with regulation of the FoxO1 and Wnt pathways. The trioleate-induced compromise of insulin sensitivity blunted the compensatory response of pancreatic ß-cells in primary rat islets. These events were associated with increases in the nuclear accumulation and transcriptional activity of FoxO1. Such effects were also observed in INS-1E cells that were subjected to oleate treatment. The overexpression of human SCD1 that was accompanied by endogenously generated oleic acid also led to an increase in the nuclear abundance of FoxO1. The mechanism of the oleate-mediated subcellular localization of FoxO1 was independent of the fatty acid receptor GPR40. Instead, the mechanism involved diversion of the active ß-catenin pool from an interaction with transcription factor 7-like 2 toward FoxO1-mediated transcription in ß-cells. Our findings identify a unique role for oleic acid in the compensatory response of pancreatic ß-cells and emphasize the importance of FoxO1 in ß-cell failure in obesity-induced insulin resistance.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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Ácido Oleico
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Transporte Proteico
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Células Secretoras de Insulina
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Beta Catenina
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Proteína Forkhead Box O1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta Mol Basis Dis
Ano de publicação:
2019
Tipo de documento:
Article