Cytochrome b5 reductase and the control of lipid metabolism and healthspan

Alejandro Martin-Montalvo; Yaning Sun; Alberto Diaz-Ruiz; Ahmed Ali; Vincent Gutierrez; Hector H. Palacios; Jessica Curtis; Emilio Siendones; Julia Ariza; Gelareh A. Abulwerdi; Xiaoping Sun; Annie X. Wang; Kevin J. Pearson; Kenneth W. Fishbein; Richard G. Spencer; Miao Wang; Xianlin Han; Morten Scheibye-Knudsen; Joe A. Baur; Howard G. Shertzer; Placido Navas; Jose Manuel Villalba; Sige Zou; Michel Bernier; Rafael de Cabo

doi:10.1038/npjamd.2016.6

Cytochrome b₅ reductase and the control of lipid metabolism and healthspan

Alejandro Martin-Montalvo, Yaning Sun, Alberto Diaz-Ruiz, Ahmed Ali, Vincent Gutierrez, Hector H. Palacios, Jessica Curtis, Emilio Siendones, Julia Ariza, Gelareh A. Abulwerdi, Xiaoping Sun, Annie X. Wang, Kevin J. Pearson, Kenneth W. Fishbein, Richard G. Spencer, Miao Wang, Xianlin Han, Morten Scheibye-Knudsen, Joe A. Baur, Howard G. ShertzerPlacido Navas, Jose Manuel Villalba, Sige Zou, Michel Bernier, Rafael de Cabo

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

Cytochrome b₅ reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender-and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan.

Original language	English
Article number	16006
Journal	npj Aging and Mechanisms of Disease
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/npjamd.2016.6
State	Published - 2016

Bibliographical note

Publisher Copyright:
© 2016 Japanese Society of Anti-Aging Medicine/Macmillan Publishers Limited.

Funding

We thank Dawn Phillips, Dawn Nines and Justine Lucas for animal care, Olga Carlson for insulin measurements, Kevin G Becker, Elin Lehrmann, William Wood and Yongqing Zhang in the microarray facility of the NIA and Alan Sartorelli for the gift of CYB5R3 plasmid used to create CYB5R3-Tg mice. Lipidomic analysis was supported by National Institute of General Medical Sciences Grant R01 GM105724. This research was supported by the Intramural Research Program of the NIH, NIA.

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Aging
National Institute of General Medical Sciences	R01 GM105724
National Institute of General Medical Sciences

ASJC Scopus subject areas

Aging
Geriatrics and Gerontology

Access to Document

10.1038/npjamd.2016.6

Cite this

Martin-Montalvo, A., Sun, Y., Diaz-Ruiz, A., Ali, A., Gutierrez, V., Palacios, H. H., Curtis, J., Siendones, E., Ariza, J., Abulwerdi, G. A., Sun, X., Wang, A. X., Pearson, K. J., Fishbein, K. W., Spencer, R. G., Wang, M., Han, X., Scheibye-Knudsen, M., Baur, J. A., ... Cabo, R. D. (2016). Cytochrome b₅ reductase and the control of lipid metabolism and healthspan. npj Aging and Mechanisms of Disease, 2(1), Article 16006. https://doi.org/10.1038/npjamd.2016.6

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abstract = "Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender-and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan.",

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Martin-Montalvo, A, Sun, Y, Diaz-Ruiz, A, Ali, A, Gutierrez, V, Palacios, HH, Curtis, J, Siendones, E, Ariza, J, Abulwerdi, GA, Sun, X, Wang, AX, Pearson, KJ, Fishbein, KW, Spencer, RG, Wang, M, Han, X, Scheibye-Knudsen, M, Baur, JA, Shertzer, HG, Navas, P, Villalba, JM, Zou, S, Bernier, M & Cabo, RD 2016, 'Cytochrome b₅ reductase and the control of lipid metabolism and healthspan', npj Aging and Mechanisms of Disease, vol. 2, no. 1, 16006. https://doi.org/10.1038/npjamd.2016.6

TY - JOUR

T1 - Cytochrome b5 reductase and the control of lipid metabolism and healthspan

AU - Martin-Montalvo, Alejandro

AU - Sun, Yaning

AU - Diaz-Ruiz, Alberto

AU - Ali, Ahmed

AU - Gutierrez, Vincent

AU - Palacios, Hector H.

AU - Curtis, Jessica

AU - Siendones, Emilio

AU - Ariza, Julia

AU - Abulwerdi, Gelareh A.

AU - Sun, Xiaoping

AU - Wang, Annie X.

AU - Pearson, Kevin J.

AU - Fishbein, Kenneth W.

AU - Spencer, Richard G.

AU - Wang, Miao

AU - Han, Xianlin

AU - Scheibye-Knudsen, Morten

AU - Baur, Joe A.

AU - Shertzer, Howard G.

AU - Navas, Placido

AU - Villalba, Jose Manuel

AU - Zou, Sige

AU - Bernier, Michel

AU - Cabo, Rafael de

PY - 2016

Y1 - 2016

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