Fine‐Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease
Open accessAbstract
Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1‐overexpressing (SIRT oe) and hepatocyte‐specific SIRT1‐KO (knockout) mice (SIRThep–/–) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24‐norursodeoxycholic acid) was tested in BDL/SIRT oe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2–/–) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRT oe mice showed exacerbated parenchymal injury whereas SIRThep–/–mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRT oe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRThep–/–hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRT oe mice. Interestingly, both SIRT1 overexpression and hepatocyte‐specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling.Conclusion:SIRT1 expression is increased during human and murine cholestasis. Fine‐tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage.
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Livers obtained from mice at 7 days after BDL do not show evidence of cirrhosis, although fibrosis is obvious.
“While livers obtained from mice at 7days after BDL do not show evidences of cirrhosis (although fibrosis is obvious in these animals50)”
From Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice (2019) · cites this paper as [50]
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- Authors
- Blokker, B. A., Maijo, M., Echeandia, M., Galduroz, M., Patterson, A. M., Ten, A., Philo, M., Schungel, R., Gutierrez‐de Juan, V., Halilbasic, E., Fuchs, C., Le Gall, G., Milkiewicz, M., Milkiewicz, P., Banales, J. M., Rushbrook, S. M., Mato, J. M., Trauner, M., Müller, M., Martínez‐Chantar, M. L., Varela‐Rey, M., & Beraza, N.
- Affiliations
- University of East Anglia (GB)
- Gut Microbes and Health Institute Strategic Programme,Quadram Institute,Norwich,United Kingdom
- Quadram Institute (GB)
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd),Derio,Spain
- Medical University of Vienna (AT)
- Metabolomics Unit,Quadram Institute,Norwich,United Kingdom
- Department of Medical Biology,Pomeranian Medical University,Szczecin,Poland
- Medical University of Warsaw (PL)
- Department of Liver and Gastrointestinal Diseases,Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque,Donostia,Spain
- Norfolk and Norwich University Hospital (GB)
- CIC bioGUNE (ES)
- Corresponding author
- Beraza, Naiara
- ORCID
- Venue
- Hepatology
- Published
- 2019-01-29
- Volume
- 69
- Issue
- 2
- Pages
- 699-716
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6492079
- OpenAlex
- W2891712242
- Cited by
- 46
- References
- 46
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 4 · 2020: 8 · 2019: 7
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Hepatology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (acceptedVersion)
- Communities in ADDI (University of the Basque Country) (submittedVersion, other-oa)
- Communities in ADDI (Universidad del Pais Vasco) (submittedVersion, cc-by)
- Hispana (submittedVersion, cc-by)
- Funders
- Fundación BBVA
- Eusko Jaurlaritza
- Ministerio de Economía y Competitividad (SAF2014‐54658‐R, PI15/01132, FIS PI12/00380, PI12/, CON14/00129, FIS PI15/01132)
- Banco Bilbao Vizcaya Argentaria
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BBS/E/F/000PR10355, BBS/E/F/00044509, (BB/J004529/1, 1937607, BBS/E/F/00044506, J004529)
- Instituto de Salud Carlos III (PS12/00402, CON14/00129, FIS PI12/00380, PI12/00380, 01132, FIS PI15/01132, PI15/01132)
- European Regional Development Fund (CON14/00129)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- SIRT1, cholestatic liver disease, cholestasis, bile acids, farnesoid X receptor, bile duct ligation, hepatocyte-specific knockout, hepatocyte apoptosis, MDR2, liver regeneration, hepatoprotection
- MeSH terms
- Animals, Bile Acids and Salts, Cholestasis, Disease Models, Animal, Humans, Case-Control Studies, Hepatocytes, Mice, Sirtuin 1
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