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 journalArticle

21 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 languageEnglish (US)
Article number16006
Journalnpj Aging and Mechanisms of Disease
Volume2
Issue number1
DOIs
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    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), [16006]. https://doi.org/10.1038/npjamd.2016.6