Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.
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.
Escande
Carlos
C
Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55902, USA.
Chini
Claudia C S
CC
Nin
Veronica
V
Dykhouse
Katherine Minter
KM
Novak
Colleen M
CM
Levine
James
J
van Deursen
Jan
J
Gores
Gregory J
GJ
Chen
Junjie
J
Lou
Zhenkun
Z
Chini
Eduardo Nunes
EN
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008136:Longevity; D051379:Mice; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D004041:Dietary Fats; D009243:NAD; D009244:NAD+ Nucleosidase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1