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S1P synthesis and signaling affects ER stress and apoptosis in insulin-producing β-cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Peter Bergsten)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Palmitate has been proposed to exert its negative effects on apoptosis via modulation of the sphingolipid pool, specifically by changing the dynamic balance between pro-apoptotic ceramide and anti-apoptotic sphingosine-1-phosphate (S1P). S1P is produced by two sphingosine kinases (SphKs), and can activate both targets inside the cell and receptors (S1PRs) on the plasma membrane. In β-cells, the cytotoxic response to cytokines is believed to be partly mediated via SphK2, and signaling through the S1PRs has been shown to protect the β-cell from this assault. In the present study, we investigated the role of SphKs as well as S1P receptors in the modulation of palmitate-induced apoptosis. MIN6 cells with reduced levels of SphK1 and 2 were established by siRNA mediated knockdown. Reduction of SphK1 attenuated secretion of S1P while reduction of SphK2 had no effect. Knockdown of SphK1, the isoform associated with production of S1P capable of signaling through S1PRs, reduced Akt signaling after palmitate exposure and augmented apoptosis. In contrast, knockdown of SphK2 completely blocked short term (<60 min) palmitate-induced phosphorylation of JNK. Reducing the levels of SphK2 also attenuated phosphorylation of eIF2α and CHOP expression, and blocked apoptosis after 48 hours exposure to palmitate. Interestingly, when S1P1/3 or S1P2 was inhibited, palmitate-induced ER stress was attenuated but apoptosis unaffected. The addition of external S1P attenuated apoptosis in the presence of S1PR inhibition but did not affect ER stress. In conclusion, SphK2 is involved in mediating palmitate-induced ER stress and apoptosis. Furthermore, activation of S1PRs may protect the β-cell from palmitate-induced apoptosis independently of ER stress.

Keyword [en]
Sphingosine-1-phosphate, sphingosine-1-phosphate receptor, sphingosine kinase, palmitate, ER stress, apoptosis
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-129572OAI: oai:DiVA.org:uu-129572DiVA: diva2:344341
Available from: 2010-08-18 Created: 2010-08-18 Last updated: 2011-07-07
In thesis
1. Palmitate-induced Apoptosis in Insulin-producing β-cells
Open this publication in new window or tab >>Palmitate-induced Apoptosis in Insulin-producing β-cells
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes is a disease characterized by the inability of pancreatic β-cells to secrete sufficient amounts of insulin to maintain normoglycemia. Increased levels of saturated fatty acids such as palmitate are believed to contribute to β-cell failure and the development of the disease. In the present thesis, mechanisms behind palmitate-induced β-cell apoptosis were explored.

Palmitate augmented insulin secretion after short exposure to the fatty acid, but attenuated the secretory response after longer exposure. Elevated levels of palmitate increased endoplasmic reticulum (ER) stress and induced apoptosis. When insulin secretion was inhibited by diazoxide, palmitate-induced ER stress and apoptosis were reduced. In comparison to palmitate, the mono-unsaturated fatty acid oleate increased neither ER stress nor apoptosis. Furthermore, shuttling of fatty acids into triglycerides and β-oxidation was favored in cells exposed to oleate compared to palmitate. When the levels of stearoyl-CoA desaturase 1 (SCD1), the enzyme responsible for conversion of saturated to mono-unsaturated fatty acids, were reduced, up-regulation of ER chaperones and components of the proteasome was observed. Cells with reduced levels of SCD1 showed increased sensitivity to palmitate, as exposure to the fatty acid increased levels of ER stress and apoptosis. Palmitate-induced apoptosis of the β-cell has been linked to alterations in sphingolipid metabolism. In cells with reduced levels of sphingosine kinase (SphK) 2, palmitate failed to induce apoptosis, and ER stress was reduced. Furthermore, SphK2 was required for the palmitate-induced activation of c-Jun N-terminal kinase (JNK). In contrast, knockdown of SphK1 sensitized the cell to palmitate-induced apoptosis independently of ER stress.

In summary, palmitate induces β-cell apoptosis, which is partly dependent on the induction of ER stress. The mechanisms investigated support the notion that increased protein load on the ER, low degree of triglyceride formation and β-oxidation, and perturbations in sphingolipid metabolism contribute to palmitate-induced apoptosis in insulin-producing β-cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 589
Keyword
ER stress, apoptosis, palmitate, sphingosine-1-phosphate, ceramide, beta-cell, fatty acid
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-129575 (URN)978-91-554-7869-8 (ISBN)
Public defence
2010-10-01, B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-09-09 Created: 2010-08-19 Last updated: 2011-07-07Bibliographically approved

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Thörn, Kristofer

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