Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression.

Published

Journal Article

We reported that the lipoapoptosis of beta-cells observed in fat-laden islets of obese fa/fa Zucker Diabetic Fatty (ZDF) rats results from overproduction of ceramide, an initiator of the apoptotic cascade and is induced by long-chain fatty acids (FA). Whereas the ceramide of cytokine-induced apoptosis may be derived from sphingomyelin hydrolysis, FA-induced ceramide overproduction seems to be derived from FA. We therefore semiquantified mRNA of serine palmitoyltransferase (SPT), which catalyzes the first step in ceramide synthesis. It was 2-3-fold higher in fa/fa islets than in +/+ controls. [3H]Ceramide formation from [3H]serine was 2.2-4. 5-fold higher in fa/fa islets. Triacsin-C, which blocks palmitoyl-CoA synthesis, and L-cycloserine, which blocks SPT activity, completely blocked [3H]ceramide formation from [3H]serine. Islets of fa/fa rats are unresponsive to the lipopenic action of leptin, which normally depletes fat and prevents FA up-regulation of SPT. To determine the role of leptin unresponsiveness in the SPT overexpression, we transferred wild type OB-Rb cDNA to their islets; now leptin completely blocked the exaggerated FA-induced increase of SPT mRNA while reducing the fat content. Beta-cell lipoapoptosis was partially prevented in vivo by treating prediabetic ZDF rats with L-cycloserine for 2 weeks. Ceramide content and DNA fragmentation both declined 40-50%. We conclude that lipoapoptosis of ZDF rats is mediated by enhanced ceramide synthesis from FA and that blockade by SPT inhibitors prevents lipoapoptosis.

Full Text

Duke Authors

Cited Authors

  • Shimabukuro, M; Higa, M; Zhou, YT; Wang, MY; Newgard, CB; Unger, RH

Published Date

  • December 4, 1998

Published In

Volume / Issue

  • 273 / 49

Start / End Page

  • 32487 - 32490

PubMed ID

  • 9829981

Pubmed Central ID

  • 9829981

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.273.49.32487

Language

  • eng

Conference Location

  • United States