Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions

Li Qiang, Ning Kon, Wenhui Zhao, Le Jiang, Colette M. Knight, Carrie Welch, Utpal Pajvani, Wei Gu, Domenico Accili

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD<sup>+</sup>-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<sup>-/-</sup> 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<sup>-/-</sup> 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. Qiang et al. show that derepression of SirT1 by Dbc1 ablation leads to elevation of the fatty acid desaturase Scd1, providing a mechanism that connects obesity with cancer.

Original languageEnglish (US)
Pages (from-to)1797-1808
Number of pages12
JournalCell Reports
Volume11
Issue number11
DOIs
StatePublished - Jun 23 2015

Fingerprint

Stearoyl-CoA Desaturase
Tumors
Ablation
Liver
Breast Neoplasms
Obesity
Neoplasms
Chemical activation
Fatty Acid Desaturases
Unsaturated Fatty Acids
Metabolism
NAD
Insulin
Tissue
Lipids
Plasmas
Insulin Resistance
stearoyl-coenzyme A
Enzymes
Incidence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions. / Qiang, Li; Kon, Ning; Zhao, Wenhui; Jiang, Le; Knight, Colette M.; Welch, Carrie; Pajvani, Utpal; Gu, Wei; Accili, Domenico.

In: Cell Reports, Vol. 11, No. 11, 23.06.2015, p. 1797-1808.

Research output: Contribution to journalArticle

Qiang, Li ; Kon, Ning ; Zhao, Wenhui ; Jiang, Le ; Knight, Colette M. ; Welch, Carrie ; Pajvani, Utpal ; Gu, Wei ; Accili, Domenico. / Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions. In: Cell Reports. 2015 ; Vol. 11, No. 11. pp. 1797-1808.
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