PMID- 24338587
OWN - NLM
STAT- MEDLINE
DCOM- 20140617
LR  - 20220331
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 59
IP  - 5
DP  - 2014 May
TI  - SIRT1 controls liver regeneration by regulating bile acid metabolism through 
      farnesoid X receptor and mammalian target of rapamycin signaling.
PG  - 1972-83
LID - 10.1002/hep.26971 [doi]
AB  - Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, 
      protein synthesis, gluconeogenesis, and bile acid (BA) homeostasis through 
      deacetylation. Here we describe that SIRT1 tightly controls the regenerative 
      response of the liver. We performed partial hepatectomy (PH) to transgenic mice 
      that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired 
      hepatocyte proliferation, BA accumulation, and profuse liver injury after 
      surgery. The damaging phenotype in SIRT mice correlated with impaired farnesoid X 
      receptor (FXR) activity due to persistent deacetylation and lower protein 
      expression that led to decreased FXR-target gene expression; small heterodimer 
      partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1. Next, we show 
      that 24-norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, 
      increases the acetylation of FXR and neighboring histones, restores 
      trimethylation of H3K4 and H3K9, and increases miR34a expression, thus 
      reestablishing BA homeostasis. Consequently, NorUDCA restored liver regeneration 
      in SIRT mice, which showed increased survival and hepatocyte proliferation. 
      Furthermore, a leucine-enriched diet restored mammalian target of rapamycin 
      (mTOR) activation, acetylation of FXR and histones, leading to an overall lower 
      BA production through SHP-inhibition of Cyp7A1 and higher transport (BSEP) and 
      detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we 
      found that human hepatocellular carcinoma (HCC) samples have increased presence 
      of SIRT1, which correlated with the absence of FXR, suggesting its oncogenic 
      potential. CONCLUSION: We define SIRT1 as a key regulator of the regenerative 
      response in the liver through posttranscriptional modifications that regulate the 
      activity of FXR, histones, and mTOR. Moreover, our data suggest that SIRT1 
      contributes to liver tumorigenesis through dysregulation of BA homeostasis by 
      persistent FXR deacetylation.
CI  - (c) 2014 by the American Association for the Study of Liver Diseases.
FAU - Garcia-Rodriguez, Juan L
AU  - Garcia-Rodriguez JL
AD  - Department of Metabolomics, CIC bioGUNE, Centro de Investigacion Biomedica en Red 
      de Enfermedades Hepaticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 
      Bizkaia, Spain.
FAU - Barbier-Torres, Lucia
AU  - Barbier-Torres L
FAU - Fernandez-Alvarez, Sara
AU  - Fernandez-Alvarez S
FAU - Gutierrez-de Juan, Virginia
AU  - Gutierrez-de Juan V
FAU - Monte, Maria J
AU  - Monte MJ
FAU - Halilbasic, Emina
AU  - Halilbasic E
FAU - Herranz, Daniel
AU  - Herranz D
FAU - Alvarez, Luis
AU  - Alvarez L
FAU - Aspichueta, Patricia
AU  - Aspichueta P
FAU - Marin, Jose J G
AU  - Marin JJ
FAU - Trauner, Michael
AU  - Trauner M
FAU - Mato, Jose M
AU  - Mato JM
FAU - Serrano, Manuel
AU  - Serrano M
FAU - Beraza, Naiara
AU  - Beraza N
FAU - Martinez-Chantar, Maria Luz
AU  - Martinez-Chantar ML
LA  - eng
GR  - R01 AT001576/AT/NCCIH NIH HHS/United States
GR  - AT-1576/AT/NCCIH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140331
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0C5V0MRU6P (farnesoid X-activated receptor)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.5.1.- (Sirt1 protein, mouse)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - Bile Acids and Salts/*metabolism/toxicity
MH  - Cell Proliferation
MH  - Homeostasis
MH  - Liver Neoplasms/etiology
MH  - *Liver Regeneration
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Receptors, Cytoplasmic and Nuclear/*physiology
MH  - Signal Transduction/*physiology
MH  - Sirtuin 1/*physiology
MH  - TOR Serine-Threonine Kinases/*physiology
PMC - PMC3999184
MID - NIHMS549320
COIS- Conflict of Interest Statement: The authors declare that they have no competing 
      financial interests. The Medical University of Graz has filed a patent on the 
      medical use of norUDCA and Michael Trauner is listed as co-inventor.
EDAT- 2013/12/18 06:00
MHDA- 2014/06/18 06:00
PMCR- 2015/05/01
CRDT- 2013/12/17 06:00
PHST- 2013/06/13 00:00 [received]
PHST- 2013/12/09 00:00 [accepted]
PHST- 2013/12/17 06:00 [entrez]
PHST- 2013/12/18 06:00 [pubmed]
PHST- 2014/06/18 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - 10.1002/hep.26971 [doi]
PST - ppublish
SO  - Hepatology. 2014 May;59(5):1972-83. doi: 10.1002/hep.26971. Epub 2014 Mar 31.