Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic ß-cells
Biol. Res
;
52: 44, 2019. graf
Article
in English
| LILACS
| ID: biblio-1019508
ABSTRACT
BACKGROUND:
Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic ß-cells that is activated by a variety of free fatty acids (FFAs). Once activated, it promotes glucose-stimulated insulin secretion (GSIS). However, increased levels of FFAs lead to lipotoxicity, inducing loss of ß-cell function. FFAR1 plays a key role in the development of type 2 diabetes (T2D), and previous studies have indicated the importance of developing anti-diabetic therapies against FFAR1, although its role in the regulation of ß-cell function remains unclear. The present study investigated the role of FFAR1 under lipotoxic conditions using palmitic acid (PA). The rat insulinoma 1 clone 832/13 (INS-1 832/13) cell line was used as a model as it physiologically resembles native pancreatic ß-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1ß), were selected as candidates to be analyzed under lipotoxic conditions.RESULTS:
We revealed that PA-induced lipotoxicity affected GSIS in INS-1 cells and negatively modulated the activity of both IRS-1 and Akt. Reduced phosphorylation of both IRS-1 S636/639 and Akt S473 was observed, in addition to decreased expression of both INSR1ß and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1ß; mRNA. Finally, PA affected localization of FFAR1 from the cytoplasm to the perinucleus.CONCLUSIONS:
In conclusion, our study suggests a novel regulatory involvement of FFAR1 in crosstalk with mTOR-Akt and IRS-1 signaling in ß-cells under lipotoxic conditions.
Full text:
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Index:
LILACS (Americas)
Main subject:
Palmitic Acid
/
Receptors, G-Protein-Coupled
/
Insulin-Secreting Cells
/
Proto-Oncogene Proteins c-akt
/
Lipid Metabolism
/
TOR Serine-Threonine Kinases
Limits:
Animals
Language:
English
Journal:
Biol. Res
Journal subject:
Biology
Year:
2019
Type:
Article
Affiliation country:
Kuwait
Institution/Affiliation country:
Dasman Diabetes Institute/KW
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