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Deleted in breast cancer–1 regulates SIRT1 activity and contributes to high-fat diet–induced liver steatosis in mice
Carlos Escande, … , Zhenkun Lou, Eduardo Nunes Chini
Carlos Escande, … , Zhenkun Lou, Eduardo Nunes Chini
Published January 11, 2010
Citation Information: J Clin Invest. 2010;120(2):545-558. https://doi.org/10.1172/JCI39319.
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Research Article Aging

Deleted in breast cancer–1 regulates SIRT1 activity and contributes to high-fat diet–induced liver steatosis in mice

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Abstract

The enzyme sirtuin 1 (SIRT1) is a critical regulator of many cellular functions, including energy metabolism. However, the precise mechanisms that modulate SIRT1 activity remain unknown. As SIRT1 activity in vitro was recently found to be negatively regulated by interaction with the deleted in breast cancer–1 (DBC1) protein, we set out to investigate whether DBC1 regulates SIRT1 activity in vivo. We found that DBC1 and SIRT1 colocalized and interacted, and that DBC1 modulated SIRT1 activity, in multiple cell lines and tissues. In mouse liver, increased SIRT1 activity, concomitant with decreased DBC1-SIRT1 interaction, was detected after 24 hours of starvation, whereas decreased SIRT1 activity and increased interaction with DBC1 was observed with high-fat diet (HFD) feeding. Consistent with the hypothesis that DBC1 is crucial for HFD-induced inhibition of SIRT1 and for the development of experimental liver steatosis, genetic deletion of Dbc1 in mice led to increased SIRT1 activity in several tissues, including liver. Furthermore, DBC1-deficient mice were protected from HFD-induced liver steatosis and inflammation, despite the development of obesity. These observations define what we believe to be a new role for DBC1 as an in vivo regulator of SIRT1 activity and liver steatosis. We therefore propose that the DBC1-SIRT1 interaction may serve as a new target for therapies aimed at nonalcoholic liver steatosis.

Authors

Carlos Escande, Claudia C.S. Chini, Veronica Nin, Katherine Minter Dykhouse, Colleen M. Novak, James Levine, Jan van Deursen, Gregory J. Gores, Junjie Chen, Zhenkun Lou, Eduardo Nunes Chini

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Figure 2

DBC1 regulates NAD-dependent SIRT1 activity.

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DBC1 regulates NAD-dependent SIRT1 activity.
(A) Isolated rat liver nucl...
(A) Isolated rat liver nuclei extracts were incubated in the absence or presence of 200 μM NAD+, or with NAD+ plus nicotinamide (2 mM), suramin (100 μM), or sirtinol (100 μM), and SIRT1 activity was measured. (B) Flag-SIRT1, full-length DBC1 (myc-DBC1-FL), and DBC1 with the leucine zipper deleted (myc-DBC1-ΔLZ) were overexpressed in 293T cells. At 24 hours after transfection, cell lysates were obtained, and SIRT1 activity was measured. NAD-dependent SIRT1 activity was expressed as a percentage of control (empty vector) activity. Protein overexpression was confirmed by Western blot. *P < 0.05 versus control; **P < 0.05 versus myc-DBC1-ΔLZ, t test. (C) MEFs derived from WT or Dbc1 KO mice were analyzed for NAD-dependent SIRT1 activity. Expression levels of SIRT1 and DBC1 were analyzed by Western blot. (D) DBC1 was knocked down in INS cells by siRNA transfection. SIRT1 activity was measured from cell lysates 72 hours after the first transfection. DBC1 knockdown was confirmed by Western blot. (E) INS cells were transfected with DBC1 siRNA, fixed after 72 hours, and stained for DBC1. Nuclei were stained with DAPI. Original magnification, ×600. (F) Endogenous p53 acetylation was analyzed by immunofluorescence after DBC1 siRNA transfection. Cells were treated with control siRNA, DBC1 siRNA, or DBC1 siRNA plus 5 mM nicotinamide (added 16 hours before fixation). Original magnification, ×600. Data are mean ± SD (n = 3). *P < 0.05, t test.

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