Beta-Cell Injury in Ncb5or-null Mice is Exacerbated by Consumption of a High-Fat Diet.

Article (PDF Available)inEuropean Journal of Lipid Science and Technology 114(3):233-243 · March 2012with25 Reads
DOI: 10.1002/ejlt.201100309 · Source: PubMed
NADH-cytochrome b5 oxidoreductase (Ncb5or) in endoplasmic reticulum (ER) is involved in fatty acid metabolism, and Ncb5or -/- mice fed standard chow (SC) are insulin-sensitive but weigh less than wild-type (WT) littermates. Ncb5or -/- mice develop hyperglycemia at about age 7 wk due to β-cell dysfunction and loss in association with saturated fatty acid (SFA) accumulation and manifestations of ER and oxidative stress. Here we report that when Ncb5or -/- mice born to heterozygous mothers fed a high fat (HF) diet continue to ingest HF, they weigh as much as SC-fed WT at age 5 wk. By age 7 wk, diabetes mellitus develops in all HF-fed versus 68% of SC-fed Ncb5or -/- mice. Islet β-cell content in age 5-wk Ncb5or -/- mice fed HF for 7 days is lower (53%) than for those fed SC (63%), and both are lower than for WT (75%, SC, vs. 69%, HF). Islet transcript levels for markers of mitochondrial biogenesis (PGC-1α) and ER stress (ATF6α) are higher in Ncb5or -/- than WT mice but not significantly affected by diet. Consuming a HF diet exacerbates Ncb5or -/- β-cell accumulation of intracellular SFA and increases the frequency of ER distention from 11% (SC) to 47% (HF), thus accelerates β-cell injury in Ncb5or -/- mice.

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Available from: Hao Zhu, Jan 06, 2014
    • "Both processes result in the build-up of (unprocessed) insulin in the secretory pathway and a worsening of ER stress. In a recent study published in this issue of the European Journal of Lipid Science and Technology, Guo et al. used another approach to restore the lipoatrophy of Ncb5or deficiency, by feeding the mice a lard-based high fat diet [27]. "
    [Show abstract] [Hide abstract] ABSTRACT: A growing body of evidence suggests that the insulin-producing beta cells in the pancreas are susceptible to saturated fatty acid-induced endoplasmic reticulum (ER) stress and apoptosis, and that this may contribute to the development of diabetes. In this issue of the European Journal of Lipid Science and Technology, Guo et al. [p. 233–234] report on accelerated beta cell dysfunction and death induced by high fat feeding of the Ncb5or knockout mouse, which lacks the ER-associated NADH-cytochrome b5 oxidoreductase and has impaired fatty acid desaturation.
    Article · Mar 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Palmitate (C16:0) induces apoptosis of insulin-secreting β-cells by processes that involve generation of reactive oxygen species, and chronically elevated blood long chain free fatty acid levels are thought to contribute to β-cell lipotoxicity and the development of diabetes mellitus. Group VIA phospholipase A2 (iPLA2β) affects β-cell sensitivity to apoptosis, and here we examined iPLA2β effects on events that occur in β-cells incubated with C16:0. Such events in INS-1 insulinoma cells were found to include activation of caspase-3, expression of stress response genes (C/EBP homologous protein and activating transcription factor 4), accumulation of ceramide, loss of mitochondrial membrane potential, and apoptosis. All of these responses were blunted in INS-1 cells that overexpress iPLA2β, which has been proposed to facilitate repair of oxidized mitochondrial phospholipids, e.g. cardiolipin (CL), by excising oxidized polyunsaturated fatty acid residues, e.g. linoleate (C18:2), to yield lysophospholipids, e.g. monolysocardiolipin (MLCL), that can be reacylated to regenerate the native phospholipid structures. Here the MLCL content of mouse pancreatic islets was found to rise with increasing iPLA2β expression, and recombinant iPLA2β hydrolyzed CL to MLCL and released oxygenated C18:2 residues from oxidized CL in preference to native C18:2. C16:0 induced accumulation of oxidized CL species and of the oxidized phospholipid (C18:0/hydroxyeicosatetraenoic acid)-glycerophosphoethanolamine, and these effects were blunted in INS-1 cells that overexpress iPLA2β, consistent with iPLA2β-mediated removal of oxidized phospholipids. C16:0 also induced iPLA2β association with INS-1 cell mitochondria, consistent with a role in mitochondrial repair. These findings indicate that iPLA2β confers significant protection of β-cells against C16:0-induced injury.
    Full-text · Article · Mar 2014