SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling

Authors

  • Juan L. García-Rodríguez,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
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  • Lucía Barbier-Torres,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
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  • Sara Fernández-Álvarez,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
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  • Virginia Gutiérrez-de Juan,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
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  • María J. Monte,

    1. Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain
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  • Emina Halilbasic,

    1. Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
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  • Daniel Herranz,

    1. Spanish National Cancer Research Center (CNIO), Madrid, Spain
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  • Luis Álvarez,

    1. Pediatric Liver Service, La Paz University Hospital, Madrid, Spain
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  • Patricia Aspichueta,

    1. Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain
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  • Jose J.G. Marín,

    1. Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain
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  • Michael Trauner,

    1. Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
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  • Jose M. Mato,

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
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  • Manuel Serrano,

    1. Spanish National Cancer Research Center (CNIO), Madrid, Spain
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  • Naiara Beraza,

    Corresponding author
    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
    2. Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain
    • Address reprint requests to: Naiara Beraza, Ph.D., Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160-Derio, Bizkaia, Spain. E-mail: nberaza@cicbiogune.es; fax 0034/944061304.

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    • These authors contributed equally to this work.

  • María Luz Martínez-Chantar

    1. Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain
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    • These authors contributed equally to this work.


  • Potential conflict of interest: 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. Prof. Trauner is also on the speakers' bureau for and received grants from Falk and Roche. He advises Phenex and Amgen. He is on the speakers' bureau for MSD and Gilead. He received grants from Albireo and Intercept.

  • Supported by grants from the Instituto de Salud Carlos III; FIS, PS12/00402 (to N.B.), NIH AT-1576 (to M.L.M.-C., and J.M.M.), ETORTEK-2010 (to M.L.M.-C), Educación Gobierno Vasco 2011 (to M.L.M.-C), PI11/01588 (to M.L.M.-C). Plan Nacional SAF2011-29851 (to JMM), Plan Nacional SAF2010-15517 (to JJ.G.-M). Basque Government IT-336-10 (to PA) and UFI 11/20 (to PA). N.B. is funded by the Program Ramon y Cajal (Ministry of Economy and Competitiveness, Spain). Ciberehd is funded by the Instituto de Salud Carlos III.

Abstract

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. (Hepatology 2014;59:1972–1983)

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