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Palmitate-induced impairments of beta-cell function are linked with generation of specific ceramide species via acylation of sphingosine
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2015 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 156, no 3, 802-812 p.Article in journal (Refereed) Published
Abstract [en]

Prolonged exposure to palmitate impairs beta-cell function and mass. One of the proposed mechanisms is alteration in ceramide generation. In the present study, exposure to palmitate induced the level of palmitoyl transferase and ceramide synthases, enzymes of the ceramide de novo and salvage pathways, and doubled total ceramide levels, which was associated with decreased insulin secretion and augmented apoptosis in MIN6 cells and human islets. By inhibiting enzymes of the pathways pharmacologically with ISP-1 or fumonisin B1 or by siRNA we showed that Cer(14:0), Cer(16:0), Cer(20:1) and Cer(24:0) species, generated by the salvage pathway, are linked to the harmful effect of palmitate on beta-cells. Oleate attenuates negative effects of palmitate on beta-cells. When oleate was included during culture of MIN6 cells with palmitate the palmitate-induced up-regulation of the enzymes of the de novo and salvage pathways was prevented resulting in normalized levels of all ceramide species except Cer(20:1). Our data suggest that enhanced ceramide generation in response to elevated palmitate levels involves both de novo and salvage pathways. However, the negative effects of palmitate on beta-cells are attributed to generation of ceramide species Cer(14:0), Cer(16:0) and Cer(24:0) via acylation of sphingosine.

Place, publisher, year, edition, pages
2015. Vol. 156, no 3, 802-812 p.
National Category
Medical and Health Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-242805DOI: 10.1210/en.2014-1467ISI: 000353272000005PubMedID: 25535826OAI: oai:DiVA.org:uu-242805DiVA: diva2:785205
Funder
Swedish Research Council, 72X-14019, 621-2011-4423
Available from: 2015-02-02 Created: 2015-02-02 Last updated: 2017-12-05Bibliographically approved

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Manukyan, LevonUbhayasekera, Sarojini J.K.A.Bergquist,, JonasSargsyan, ErnestBergsten, Peter

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