Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease
| Autor: | Monica Maijo, Anna Ten, Michael Trauner, Claudia D. Fuchs, Mikel Galduroz, Emina Halilbasic, Naiara Beraza, Virginia Gutiérrez-de Juan, Marta Varela-Rey, Marta Echeandia, Piotr Milkiewicz, Rebecca Schungel, Mark Philo, Michael Müller, Jesus M. Banales, Gwénaëlle Le Gall, Britt A Blokker, Simon M. Rushbrook, Angela M. Patterson, Malgorzata Milkiewicz, María L. Martínez-Chantar, José M. Mato |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
sclerosing cholangitis farnesoid x receptor Mice chemistry.chemical_compound 0302 clinical medicine obeticholic acid Sirtuin 1 norursodeoxycholic acid 2. Zero hunger Cholestasis Bile acid biology pathogenesis Obeticholic acid Liver regeneration Ursodeoxycholic acid 3. Good health ursodeoxycholic acid bile-acid metabolism Knockout mouse Original Article 030211 gastroenterology & hepatology hormones hormone substitutes and hormone antagonists medicine.drug medicine.medical_specialty medicine.drug_class proliferation growth-factor Bile Acids and Salts 03 medical and health sciences fxr Internal medicine medicine Animals Humans Hepatology Original Articles medicine.disease Disease Models Animal Autoimmune Cholestatic and Biliary Disease 030104 developmental biology Endocrinology chemistry Case-Control Studies Hepatocytes biology.protein Farnesoid X receptor |
| Zdroj: | Hepatology (Baltimore, Md.) Addi. Archivo Digital para la Docencia y la Investigación instname |
| Popis: | 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 (SIRToe) 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/SIRToe 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. SIRToe mice showed exacerbated parenchymal injury whereas SIRThep-/- mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRToe 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/SIRToe 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. Supported by the Biotechnology and Biological Sciences Research Council (BBSRC) by the BBSRC Institute Strategic Programme Gut Health and Food Safety and Gut Microbes and Health BBS/E/F/00044509 (to N.B.), the NRP Science Links Seed Corn Fund grant (to N.B., S.R.), Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Partnership programme (to N.B., A.T.), and Instituto de Salud Carlos III; FIS, PS12/00402 (to N.B. and M.V.R.). N.B. was funded by the BBSRC Institute Strategic Programme Gut Health and Food Safety BB/J004529/1, the Program Ramon y Cajal (Ministry of Economy and Competitiveness, Spain) and Ikerbaske foundation (Basque government, Spain). FIS PI12/00380, FIS PI15/01132, and Miguel Servet Program CON14/00129 cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER; to J.M.B.). Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), MINECO: SAF2014-54658-R, EITB Maratoia BIO15/CA/014 (to M.L.M.C.) Asociacion Espanola contra el Cancer. Ciberehd is funded by the Instituto de Salud Carlos III. Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (to M.V.R.). M.E. and M.G. were supported by the Camara de Comercio de Navarra. |
| Databáze: | OpenAIRE |
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