Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells
Abstract Background: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic β-cells that is activated by a variety of free fatty acids (FFAs). Once activated, it promotes glucose-stimulated insulin secretion (GSIS). However, increased levels...
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Sociedad de Biología de Chile
2019
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oai:scielo:S0716-976020190001002412019-10-10Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cellsMarafie,Sulaiman K.Al-Shawaf,Eman M.Abubaker,JehadArefanian,Hossein Palmitic acid Lipotoxicity Insulin resistance Type 2 diabetes FFAR1 mTOR Akt IRS-1 INSR β-cells Abstract Background: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic β-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 β-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 β-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 β-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1β), 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 INSR1β and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1β 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 β-cells under lipotoxic conditions.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.52 20192019-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602019000100241en10.1186/s40659-019-0253-4 |
| institution |
Scielo Chile |
| collection |
Scielo Chile |
| language |
English |
| topic |
Palmitic acid Lipotoxicity Insulin resistance Type 2 diabetes FFAR1 mTOR Akt IRS-1 INSR β-cells |
| spellingShingle |
Palmitic acid Lipotoxicity Insulin resistance Type 2 diabetes FFAR1 mTOR Akt IRS-1 INSR β-cells Marafie,Sulaiman K. Al-Shawaf,Eman M. Abubaker,Jehad Arefanian,Hossein Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells |
| description |
Abstract Background: Free fatty acid receptor 1 (FFAR1) is G-protein coupled receptor predominantly expressed in pancreatic β-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 β-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 β-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 β-cells. Key players of the insulin signaling pathway, such as mTOR, Akt, IRS-1, and the insulin receptor (INSR1β), 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 INSR1β and FFAR1. Moreover, transient knockdown of FFAR1 led to a reduction in IRS-1 mRNA expression and an increase in INSR1β 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 β-cells under lipotoxic conditions. |
| author |
Marafie,Sulaiman K. Al-Shawaf,Eman M. Abubaker,Jehad Arefanian,Hossein |
| author_facet |
Marafie,Sulaiman K. Al-Shawaf,Eman M. Abubaker,Jehad Arefanian,Hossein |
| author_sort |
Marafie,Sulaiman K. |
| title |
Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells |
| title_short |
Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells |
| title_full |
Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells |
| title_fullStr |
Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells |
| title_full_unstemmed |
Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells |
| title_sort |
palmitic acid-induced lipotoxicity promotes a novel interplay between akt-mtor, irs-1, and ffar1 signaling in pancreatic β-cells |
| publisher |
Sociedad de Biología de Chile |
| publishDate |
2019 |
| url |
http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602019000100241 |
| work_keys_str_mv |
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| _version_ |
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