Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease
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 r...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2019 |
| Country: | España |
| Institution: | Universidad del País Vasco |
| Repository: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/32113 |
| Online Access: | http://hdl.handle.net/10810/32113 |
| Access Level: | Open access |
| Keyword: | farnesoid x receptor bile-acid metabolism norursodeoxycholic acid sclerosing cholangitis ursodeoxycholic acid obeticholic acid growth-factor fxr proliferation pathogenesis |
| _version_ | 1878732611870785536 |
|---|---|
| author | Blokker, Britt A. |
| author2 | Maijo, Monica Echeandia, Marta Galduroz, Mikel Patterson, Angela M. Ten, Anna Philo, Mark Schungel, Rebecca Gutiérrez de Juan, Virginia Halilbasic, Emina Fuchs, Claudia Le Gall, Gwenaelle Milkiewicz, Malgorzata Milkiewicz, Piotr Bañales Asurmendi, Jesús María Rushbrook, Simon M. Mato, José M. Trauner, Michael Müller, Michael Martínez Chantar, María Luz Varela Rey, Marta Beraza, Naiara |
| author2_role | author author author author author author author author author author author author author author author author author author author author author |
| author_browse | Bañales Asurmendi, Jesús María Beraza, Naiara Blokker, Britt A. Echeandia, Marta Fuchs, Claudia Galduroz, Mikel Gutiérrez de Juan, Virginia Halilbasic, Emina Le Gall, Gwenaelle Maijo, Monica Martínez Chantar, María Luz Mato, José M. Milkiewicz, Malgorzata Milkiewicz, Piotr Müller, Michael Patterson, Angela M. Philo, Mark Rushbrook, Simon M. Schungel, Rebecca Ten, Anna Trauner, Michael Varela Rey, Marta |
| author_facet | Blokker, Britt A. Maijo, Monica Echeandia, Marta Galduroz, Mikel Patterson, Angela M. Ten, Anna Philo, Mark Schungel, Rebecca Gutiérrez de Juan, Virginia Halilbasic, Emina Fuchs, Claudia Le Gall, Gwenaelle Milkiewicz, Malgorzata Milkiewicz, Piotr Bañales Asurmendi, Jesús María Rushbrook, Simon M. Mato, José M. Trauner, Michael Müller, Michael Martínez Chantar, María Luz Varela Rey, Marta Beraza, Naiara |
| author_role | author |
| collection | Addi. Archivo Digital para la Docencia y la Investigación |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_465ef94f221f2cd007406df875f59192 |
| institution | Universidad del País Vasco |
| instname_str | Universidad del País Vasco |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:addi.ehu.eus:10810/32113 |
| publishDate | 2019 |
| publishDateSort | 2019 |
| publisher | Wiley |
| publisherStr | Wiley |
| reponame_str | Addi. Archivo Digital para la Docencia y la Investigación |
| spelling | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease Blokker, Britt A. Maijo, Monica Echeandia, Marta Galduroz, Mikel Patterson, Angela M. Ten, Anna Philo, Mark Schungel, Rebecca Gutiérrez de Juan, Virginia Halilbasic, Emina Fuchs, Claudia Le Gall, Gwenaelle Milkiewicz, Malgorzata Milkiewicz, Piotr Bañales Asurmendi, Jesús María Rushbrook, Simon M. Mato, José M. Trauner, Michael Müller, Michael Martínez Chantar, María Luz Varela Rey, Marta Beraza, Naiara farnesoid x receptor bile-acid metabolism norursodeoxycholic acid sclerosing cholangitis ursodeoxycholic acid obeticholic acid growth-factor fxr proliferation pathogenesis 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. Wiley http://hdl.handle.net/10810/32113 |
| spellingShingle | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease Blokker, Britt A. farnesoid x receptor bile-acid metabolism norursodeoxycholic acid sclerosing cholangitis ursodeoxycholic acid obeticholic acid growth-factor fxr proliferation pathogenesis |
| title | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease |
| title_full | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease |
| title_fullStr | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease |
| title_full_unstemmed | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease |
| title_short | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease |
| title_sort | Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease |
| topic | farnesoid x receptor bile-acid metabolism norursodeoxycholic acid sclerosing cholangitis ursodeoxycholic acid obeticholic acid growth-factor fxr proliferation pathogenesis |
| topic_facet | farnesoid x receptor bile-acid metabolism norursodeoxycholic acid sclerosing cholangitis ursodeoxycholic acid obeticholic acid growth-factor fxr proliferation pathogenesis |
| url | http://hdl.handle.net/10810/32113 |