title: Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions.
abstract: Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1(-/-) mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired activation of the master tumor suppressor p53 and treatment with an Scd1 inhibitor extended survival of tumor-prone TP53(-/-) mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression mediated by hepatic SirT1 and resulting in the activation of a key lipid synthetic enzyme, with potential therapeutic implications.
authors.affiliation: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Kon
authors.affiliation: Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Colette M
authors.initials: CM
authors.lastname: Knight
authors.affiliation: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.affiliation: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Utpal
authors.initials: U
authors.lastname: Pajvani
authors.affiliation: Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: wg8@columbia.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: da230@cumc.columbia.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C491992:BRINP1 protein, mouse; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1