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Palmitate-induced beta cell apoptosis and development of the unfolded protein response
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
(English)Manuscript (Other academic)
Abstract [en]
Elevated levels of lipids are detrimental for beta cell function and mass. Accentuation or attenuation of these effects has been proposed to depend on promoting lipid accumulation or oxidation, respectively. In the present study we investigated if enhanced and reduced beta cell apoptosis observed in response to altered lipid metabolism involves modulation of the unfolded protein response (UPR). INS-1E cells were cultured in the presence of 0.5 mM palmitate and 3, 11 or 25 mM glucose for 3 or 24 hours. Cells cultured in the presence of palmitate and 11 mM glucose were additionally exposed to AMPK-agonist AICAR or CPT1-inhibitior etomoxir. After culture, apoptosis and expression levels of UPR markers were determined. Apoptosis was induced 3- and 5-fold in cells cultured in the presence of palmitate and 11 or 25 mM glucose, respectively. No induction was observed in cells cultured in the presence of palmitate and 3 mM glucose. Despite the glucose-dependency of palmitate-induced beta cell apoptosis, expression levels of UPR markers were not altered by varying the glucose concentration. In addition, although AICAR reduced apoptosis in palmitate-treated cells and etomoxir accentuated apoptosis in cells exposed to the fatty acid, UPR markers were neither affected by AICAR nor etomoxir. We conclude that under conditions, which direct palmitate-exposed cells either towards lipid oxidation or accumulation, apoptosis but not activation of the UPR is altered. It is hypothesized that palmitate-induced activation of the UPR is not a major determinant of apoptosis in beta cells exposed to the fatty acid.
Keyword [en]
ER stress, unfolded protein response, glucolipotoxicity, apoptosis, INS-1E pancreatic beta cells
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-98363OAI: oai:DiVA.org:uu-98363DiVA: diva2:174253
Available from: 2009-02-19 Created: 2009-02-19 Last updated: 2010-01-14
In thesis
1. Glucose, Palmitate and Apolipoprotein CIII-induced Effects on Insulin-Producing β-cells
Open this publication in new window or tab >>Glucose, Palmitate and Apolipoprotein CIII-induced Effects on Insulin-Producing β-cells
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background and aims: Type 2 diabetes mellitus results from complex interplay between genetic predisposition and environmental factors that together promote impairment of insulin-producing β-cells. Elevated levels of glucose, fatty acid palmitate and apolipoprotein CIII (apoCIII) are implicated in this process. To delineate effects of these factors, the role of enhanced carnitine palmitoyltransferase 1 (CPT1) expression in glucolipotoxic cells, glucose-dependency of the unfolded protein response (UPR) in palmitate-induced apoptosis and activation of mitogen activated protein kinases (MAPKs) in apoCIII-induced apoptosis were evaluated. In addition, protein profiles of β-cell exposed to elevated levels of glucose or palmitate were generated to identify proteins regulated by these nutrients.

Methodology: INS-1E cells were cultured at different glucose concentrations in the absence or presence of palmitate or apoCIII for up to 48 hours. CPT1 was over-expressed with a Tet-ON regulated adenovirus. In cells exposed to apoCIII, inhibitors of MAPKs p38 or ERK1/2 were included during culture. After culture, apoptosis, insulin secretion, expression of UPR-markers and MAPKs and protein profiles were determined.

Results: INS-1E cells exposed to elevated levels of glucose and palmitate showed deranged insulin secretion with increased insulin secretion at non-stimulatory glucose level, enhanced apoptosis and induced expression of UPR-markers. Over-expression of CPT1 reduced basal insulin secretion and attenuated apoptosis. Palmitate-induced apoptosis was accentuated by increasing the culture glucose concentration. Markers of UPR were not modulated by the glucose concentration in INS-1E cell exposed to palmitate, however. ApoCIII-induced apoptosis in INS-1E cells was accompanied by activation of p38 and ERK1/2. Protein profiling of INS-1E cells exposed to elevated levels of glucose or palmitate revealed changes in expression of multiple β-cell proteins implicated in glucose metabolism, defence against reactive oxygen species, protein translation/folding/degradation and insulin granular trafficking.

Conclusions: Over-expression of CPT1 counteracts β-cell glucolipotoxicity. Activation of UPR is not a major determinant for palmitate-induced β-cell apoptosis. ApoCIII-induced β-cell apoptosis involves activation of MAPKs. The identified differentially expressed proteins indicate a central role of altered glucose metabolism and protein synthesis in gluco- and lipotoxic β-cells and may provide specific molecular mechanisms offering new ways of treating the disease.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 429
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-98367 (URN)978-91-554-7440-9 (ISBN)
Public defence
2009-04-03, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-03-13 Created: 2009-02-19 Last updated: 2009-05-07Bibliographically approved

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