Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells

Wang, Wenfang; Guo, Ying; Xu, Ming; Huang, Han-Hung; Novikova, Lesya; Larade, Kevin; Jiang, Zhigang; Thayer, Terri C.; Frontera, Jennifer R.; Aires, Daniel; Ding, Huanyu; Turk, John; Mathews, Clayton E.; Bunn, H. Franklin; Stehno‐Bittel, Lisa; Zhu, Hao

doi:10.1016/j.bbadis.2011.07.016

Cited by 18 publications

(31 citation statements)

References 54 publications

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“…Naturally occurring polymorphism’s in human NCB5OR have been shown result in increased proteasomal degradation (10). Transgenic mice globally deficient in NCB5OR (GKO) have low birth weight (beginning at 2 weeks of age), petite skeletal structure/build, impaired lipid storage and lipoatrophy, hypermetabolism, mitochondrial dysfunction, and early-onset diabetes from necrotic beta cell loss when compared to normal or wild-type (WT) control mice (11–14). We recently discovered that global loss of NCB5OR results in mild to moderate anemia, significant changes in iron related pathways, and iron deficiency in iron rich tissues such as the spleen and liver (15).…”

Section: Introductionmentioning

confidence: 99%

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

et al. 2016

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Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. 59Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 weeks and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain.

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Section: Introductionmentioning

confidence: 99%

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

et al. 2016

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“…Although the molecular and cellular mechanisms underlying FFA-induced ␤-cell apoptosis are not fully understood, participating processes include generation of reactive oxygen species (ROS) and mitochondrial dysfunction (8 -11), production of ceramide and nitric oxide (NO) (4,12), and induction of endoplasmic reticulum stress (13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Group VIA Phospholipase A2 Mitigates Palmitate-induced β-Cell Mitochondrial Injury and Apoptosis

Song

Wohltmann

Tan

et al. 2014

Journal of Biological Chemistry

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Background: Lipid-induced ␤-cell loss contributes to type 2 diabetes mellitus (T2DM). Results: Palmitate-induced ␤-cell lipid oxidation, mitochondrial dysfunction, and apoptosis correlate inversely with expression of iPLA 2 ␤, which associates with mitochondria, generates monolysocardiolipin, and lowers oxidized phospholipid content. Conclusion: iPLA 2 ␤ mitigates palmitate-induced ␤-cell mitochondrial injury and apoptosis and may facilitate repair of oxidized lipids. Significance: Understanding lipid-induced ␤-cell loss could lead to T2DM therapies.

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“…Prediabetic Ncb5or −/− mice exhibit β‐cell dysfunction manifest by reduced islet insulin content, impaired glucose‐stimulated insulin secretion, and glucose intolerance 11. We have recently demonstrated that Ncb5or −/− β‐cell defects include increased intracellular free SFA levels and manifestations of ER and oxidative stress and that progression of ER distention correlates with the magnitude of β‐cell dysfunction and loss in prediabetic Ncb5or −/− mice 16.…”

Section: Introductionmentioning

confidence: 91%

Beta‐cell injury in Ncb5or‐null mice is exacerbated by consumption of a high‐fat diet

Guo

Deng

et al. 2011

Euro J Lipid Sci & Tech

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Summary 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 weeks due to β-cell dysfunction and loss associated with saturated fatty acid 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 weeks. By age 7 weeks, diabetes mellitus develops in all HF-fed vs. 68% of SC-fed Ncb5or−/− mice. Islet β-cell content in age 5-week 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 saturated fatty acids 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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Development of diabetes in lean Ncb5or-null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells

Cited by 18 publications

References 54 publications

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Group VIA Phospholipase A2 Mitigates Palmitate-induced β-Cell Mitochondrial Injury and Apoptosis

Beta‐cell injury in Ncb5or‐null mice is exacerbated by consumption of a high‐fat diet

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