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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Wang, WenFang^1,3,5  Guo, Ying^2,9  Xu, Ming¹  Huang, Han-Hung¹  Novikova, Lesya¹  Larade, Kevin⁶  Jiang, Zhi-Gang⁶  Thayer, Terri C.⁷  Frontera, Jennifer R.³  Aires, Daniel³  Ding, Helin⁹  Turk, John⁸  Mathews, Clayton E.⁷  Bunn, H. Franklin⁶  Stehno-Bittel, Lisa¹  Zhu, Hao^1,2,4 

[1] Univ Kansas, Med Ctr, Dept Phys Therapy & Rehabil Sci, Kansas City, KS 66160 USA

[2] Univ Kansas, Med Ctr, Dept Clin Lab Sci, Kansas City, KS 66160 USA

[3] Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66160 USA

[4] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66160 USA

[5] Univ Kansas, Med Ctr, Dept Pathol, Kansas City, KS 66160 USA

[6] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[7] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA

[8] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA

[9] Sun Yat Sen Univ, Affiliated Hosp 2, Dept Endocrinol, Guangzhou 510275, Guangdong, Peoples R China

关键词: Oxidative stress;    ER stress;    Free fatty acid;    Diabetes;    Beta-cell;   

DOI  :  10.1016/j.bbadis.2011.07.016

来源: Elsevier

【 摘 要 】

NADH-cytochrome b5 oxidoreductase (Ncb5or) is an endoplasmic reticulum (ER)-associated redox enzyme involved in fatty acid metabolism, and phenotypic abnormalities of Ncb5or(-/-) mice include diabetes and lipoatrophy. These mice are lean and insulin-sensitive but become hyperglycemic at age 7 weeks as a result of beta-cell dysfunction and loss. Here we examine early cellular and molecular events associated with manifestations of beta-cell defects in Ncb5or(-/-) - mice. We observe lower islet beta-cell content in pancreata at age 4 weeks and prominent ER distention in beta-cells by age 5 weeks. Ultrastructural changes progress rapidly in severity from age 5 to 6 weeks, and their frequency rises from 10% of beta-cells at 5 weeks to 33% at 6 weeks. These changes correlate temporally with the onset of diabetes. ER stress responses and lipid load in Ncb5or(-/-) beta-cells were assessed with isolated islets from mice at age 5 weeks. Expression levels of the stress marker protein Grp78/BiP and of phosphorylated eIF2 alpha protein were found to be reduced, although their transcript levels did not decline. This pattern stands in contrast to the canonical unfolded protein response. Ncb5or(-/-) beta-cells also accumulated higher intracellular levels of palmitate and other free fatty acids and exhibited greater reactive oxygen species production than wild-type cells. An alloxan-susceptible genetic background was found to confer accelerated onset of diabetes in Ncb5or(-/-) mice. These findings provide the first direct evidence that manifestations of diabetes in lean Ncb5or(-/-) mice involve saturated free fatty acid overload of beta-cells and ER and oxidative stress responses. (C) 2011 Elsevier B.V. All rights reserved.

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