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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 8

DBC1 controls oleate/palmitate-induced cellular steatosis through a SIRT1-dependent mechanism.

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DBC1 controls oleate/palmitate-induced cellular steatosis through a SIRT...
(A) Lipid accumulation levels in primary hepatocytes isolated from WT and Dbc1 KO mice. An average of 3 different experiments is shown. *P < 0.05, **P < 0.1 versus control, t test. (B) Lipid accumulation in MEFs derived from WT and Dbc1 KO mice. Shown is 1 representative experiment of 4. (C) Lipid accumulation in HEPG2 cells. *P < 0.05, **P < 0.1, t test. n = 3. (D) Lipid accumulation in HEPG2 cells. Cells were transfected with control or DBC1 siRNA and then incubated with oleate/palmitate. SIRT1 activity was measured; values were normalized to those from control siRNA transfection. Protein levels were evaluated by Western blot. *P < 0.05, t test. n = 3. (E) Lipid accumulation in HEPG2 cells. Cells were transfected with control, SIRT1, and DBC1 siRNAs and then incubated with oleate/palmitate. *P < 0.05, **P < 0.1 versus control siRNA, t test. n = 4. (F and G) Effect of DBC1 overexpression on lipid accumulation in HEPG2 (F) and 293T (G) cells. Cells were transfected with empty vector or myc-DBC1 for 48 hours. During the last 16 hours of transfection, cells were incubated with different concentrations of oleate/palmitate (2:1 ratio). *P < 0.05, t test. n = 3. Data are mean ± SD.

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