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Matthew A Stroh, Michelle K Winter, Russell H Swerdlow, Kenneth E McCarson, Hao Zhu
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...
August 2016: Metabolic Brain Disease
Fanni S Kálmán, Beáta Lizák, Szilvia K Nagy, Tamás Mészáros, Veronika Zámbó, József Mandl, Miklós Csala, Eva Kereszturi
NADH cytochrome b5 oxidoreductase (Ncb5or) protects β-cells against oxidative stress and lipotoxicity. The predominant phenotype of lean Ncb5or-null mouse is insulin-dependent diabetes due to β-cell death. This suggests the putative role of NCB5OR polymorphism in human diabetes. Therefore, we aimed to investigate the effect of natural missense mutations on the expression of human NCB5OR. Protein and mRNA levels of five non-synonymous coding variants were analyzed in transfected HEK293 and HepG2 cells. Although the mRNA levels were only slightly affected by the mutations, the amount of Ncb5or protein was largely reduced upon two Glu to Gly replacements in the third exon (p...
July 2013: Biochimie
Supratim Mukherjee, Sumit Sen Santara, Shantanabha Das, Moumita Bose, Jayasree Roy, Subrata Adak
NAD(P)H cytochrome b(5) oxidoreductase (Ncb5or), comprising cytochrome b(5) and cytochrome b(5) reductase domains, is widely distributed in eukaryotic organisms. Although Ncb5or plays a crucial role in lipid metabolism of mice, so far no Ncb5or gene has been reported in the unicellular parasitic protozoa Leishmania species. We have cloned, expressed, and characterized Ncb5or gene from Leishmania major. Steady state catalysis and spectral studies show that NADH can quickly reduce the ferric state of the enzyme to the ferrous state and is able to donate an electron(s) to external acceptors...
October 12, 2012: Journal of Biological Chemistry
Ying Guo, Ming Xu, Bin Deng, Jennifer R Frontera, Karen L Kover, Daniel Aires, Helin Ding, Susan E Carlson, John Turk, Wenfang Wang, Hao Zhu
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...
March 2012: European Journal of Lipid Science and Technology: EJLST
Wenfang Wang, Ying Guo, Ming Xu, Han-Hung Huang, Lesya Novikova, Kevin Larade, Zhi-Gang Jiang, Terri C Thayer, Jennifer R Frontera, Daniel Aires, Helin Ding, John Turk, Clayton E Mathews, H Franklin Bunn, Lisa Stehno-Bittel, Hao Zhu
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 β-cell dysfunction and loss. Here we examine early cellular and molecular events associated with manifestations of β-cell defects in Ncb5or(-/-) mice. We observe lower islet β-cell content in pancreata at age 4 weeks and prominent ER distention in β-cells by age 5 weeks...
November 2011: Biochimica et Biophysica Acta
Ming Xu, WenFang Wang, Jennifer R Frontera, Melanie C Neely, Jianghua Lu, Daniel Aires, Fong-Fu Hsu, John Turk, Russell H Swerdlow, Susan E Carlson, Hao Zhu
The endoplasmic reticulum-associated NADH cytochrome b(5) oxidoreductase (Ncb5or) is widely distributed in animal tissues. Ncb5or(-/-) mice develop diabetes at age 7 weeks and have increased susceptibility to the diabetogenic oxidant streptozotocin. Ncb5or deficiency also results in lipoatrophy and increased hepatocyte sensitivity to cytotoxic effects of saturated fatty acids. Here we investigate the mechanisms of these phenomena in prediabetic Ncb5or(-/-) mice and find that, despite increased rates of fatty acid uptake and synthesis and higher stearoyl-CoA desaturase (SCD) expression, Ncb5or(-/-) liver accumulates less triacylglycerol (TAG) than wild type (WT)...
April 1, 2011: Journal of Biological Chemistry
Bin Deng, Sudharsan Parthasarathy, WenFang Wang, Brian R Gibney, Kevin P Battaile, Scott Lovell, David R Benson, Hao Zhu
NADH cytochrome b(5) oxidoreductase (Ncb5or) is found in animals and contains three domains similar to cytochrome b(5) (b(5)), CHORD-SGT1 (CS), and cytochrome b(5) reductase (b(5)R). Ncb5or has an important function, as suggested by the diabetes and lipoatrophy phenotypes in Ncb5or null mice. To elucidate the structural and functional properties of human Ncb5or, we generated its individual b(5) and b(5)R domains (Ncb5or-b(5) and Ncb5or-b(5)R, respectively) and compared them with human microsomal b(5) (Cyb5A) and b(5)R (Cyb5R3)...
September 24, 2010: Journal of Biological Chemistry
Yongzhao Zhang, Kevin Larade, Zhi-Gang Jiang, Susumu Ito, Wenfang Wang, Hao Zhu, H Franklin Bunn
NCB5OR is a novel flavoheme reductase with a cytochrome b5-like domain at the N-terminus and a cytochrome b5 reductase-like domain at the C terminus. Ncb5or knock-out mice develop insulin deficient diabetes and loss of white adipose tissue. Ncb5or(-/-) mice have impairment of Delta9 fatty acid desaturation with elevated ratios of palmitate to palmitoleate and stearate to oleate. In this study we assess the role of the endoplasmic reticulum (ER) stress response in mediating lipotoxicity in Ncb5or(-/-) mice. The ER stress response was assessed by induction of BiP, ATF3, ATF6, XBP-1, and C/EBP homologous protein (CHOP)...
January 2010: Journal of Lipid Research
Kevin Larade, Zhigang Jiang, Yongzhao Zhang, WenFang Wang, Susan Bonner-Weir, Hao Zhu, H Franklin Bunn
Targeted ablation of the novel flavoheme reductase Ncb5or knock-out (KO) results in progressive loss of pancreatic beta-cells and white adipose tissue over time. Lipoatrophy persisted in KO animals in which the confounding metabolic effects of diabetes were eliminated by islet transplantation (transplanted knockout (TKO)). Lipid profiles in livers prepared from TKO animals were markedly deficient in triglycerides and diacylglycerides. Despite enhanced expression of stearoyl-Co-A desaturase-1, levels of palmitoleic and oleic acids (Delta9 fatty acid desaturation) were decreased in TKO relative to wild type controls...
October 24, 2008: Journal of Biological Chemistry
Kevin Larade, Zhi-gang Jiang, Andre Dejam, Hao Zhu, H Franklin Bunn
The novel reductase NCB5OR (NADPH cytochrome b5 oxidoreductase) resides in the ER (endoplasmic reticulum) and may protect cells against ER stress. Levels of BiP (immunoglobulin heavy-chain-binding protein), CHOP (CCAAT/enhancer-binding protein homologous protein) and XBP-1 (X-box-binding protein-1) did not differ in WT (wild-type) and KO (Ncb5or-null) tissues or MEFs (mouse embryonic fibroblasts), and XBP-1 remained unspliced. MEFs treated with inducers of ER stress demonstrated no change in Ncb5or expression and expression of ER-stress-induced genes was not enhanced...
June 15, 2007: Biochemical Journal
Kevin Larade, H Franklin Bunn
Ncb5or is a ubiquitously expressed gene required for beta-cell survival in mice. Examination of mouse tissues demonstrated high levels of expression in the pancreas, heart and kidney. A transcription start site was identified 149 bp upstream from the start codon and transient expression analysis in betaTC3 cells indicated the presence of a core promoter located within 348 bp upstream of this site. Deletion of Region C (-216/-157) resulted in a significant decrease in promoter activity and specific nucleotides located in a region designated C2 were demonstrated to be critical for complex binding...
May 2006: Biochimica et Biophysica Acta
Gitte Andersen, Lise Wegner, Christian Schack Rose, Jianxin Xie, Hao Zhu, Kevin Larade, Anders Johansen, Jakob Ek, Jeannet Lauenborg, Thomas Drivsholm, Knut Borch-Johnsen, Peter Damm, Torben Hansen, H Franklin Bunn, Oluf Pedersen
Recent data show that homozygous Ncb5or(-/-) knock-out mice present with an early-onset nonautoimmune diabetes phenotype. Furthermore, genome-wide scans have reported linkage to the chromosome 6q14.2 region close to the human NCB5OR. We therefore considered NCB5OR to be a biological and positional candidate gene and examined the coding region of NCB5OR in 120 type 2 diabetic patients and 63 patients with maturity-onset diabetes of the young using denaturing high-performance liquid chromatography. We identified a total of 22 novel nucleotide variants...
November 2004: Diabetes
Jianxin Xie, Hao Zhu, Kevin Larade, Annie Ladoux, Ayden Seguritan, Michelle Chu, Susumu Ito, Roderick T Bronson, Edward H Leiter, Chen-Yu Zhang, Evan D Rosen, H Franklin Bunn
NCB5OR is a highly conserved NAD(P)H reductase that contains a cytochrome b5-like domain at the N terminus and a cytochrome b5 reductase-like domain at the C terminus. The enzyme is located in the endoplasmic reticulum (ER) and is widely expressed in organs and tissues. Targeted inactivation of this gene in mice has no impact on embryonic or fetal viability. At 4 weeks of age, Ncb5or-/- mice have normal blood glucose levels but impaired glucose tolerance. Isolated Ncb5or-/- islets have markedly impaired glucose- or arginine-stimulated insulin secretion...
July 20, 2004: Proceedings of the National Academy of Sciences of the United States of America
Hao Zhu, Kevin Larade, Timothy A Jackson, Jianxin Xie, Annie Ladoux, Helmut Acker, Utta Berchner-Pfannschmidt, Joachim Fandrey, Andrew R Cross, Gudrun S Lukat-Rodgers, Kenton R Rodgers, H Franklin Bunn
The NAD(P)H cytochrome b5 oxidoreductase, Ncb5or (previously named b5+b5R), is widely expressed in human tissues and broadly distributed among the animal kingdom. NCB5OR is the first example of an animal flavohemoprotein containing cytochrome b5 and chrome b5 reductase cytodomains. We initially reported human NCB5OR to be a 487-residue soluble protein that reduces cytochrome c, methemoglobin, ferricyanide, and molecular oxygen in vitro. Bioinformatic analysis of genomic sequences suggested the presence of an upstream start codon...
July 16, 2004: Journal of Biological Chemistry
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