Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease

被引：49

作者：

Blokker, Britt A. ^{[1
,2
]}

Maijo, Monica ^{[2
]}

Echeandia, Marta ^{[2
]}

Galduroz, Mikel ^{[2
]}

Patterson, Angela M. ^{[2
]}

Ten, Anna ^{[2
]}

Philo, Mark ^{[3
]}

Schungel, Rebecca ^{[2
,4
]}

Gutierrez-de Juan, Virginia ^{[5
]}

Halilbasic, Emina ^{[6
]}

Fuchs, Claudia ^{[6
]}

Le Gall, Gwenaelle ^{[3
]}

Milkiewicz, Malgorzata ^{[7
]}

Milkiewicz, Piotr ^{[8
]}

Banales, Jesus M. ^{[9
]}

Rushbrook, Simon M. ^{[10
]}

Mato, Jose M. ^{[5
]}

Trauner, Michael ^{[6
]}

Mueller, Michael ^{[1
]}

Luz Martinez-Chantar, Maria ^{[5
]}

Varela-Rey, Marta ^{[5
]}

Beraza, Naiara ^{[2
,5
]}

机构：

[1] Univ East Anglia, Norwich Med Sch, Norwich, Norfolk, England

[2] Quadram Inst, Strateg Programme, Gut Microbes & Hlth Inst, Norwich Res Pk, Norwich NR4 7UA, Norfolk, England

[3] Quadram Inst, Metabol Unit, Norwich, Norfolk, England

[4] Univ Appl Sci Munster, Dept Food Nutr Facil, Munster, Germany

[5] Ctr Investigac Biomed Red Enfermedades Hepat Dige, CIC bioGUNE, Derio, Spain

[6] Med Univ Vienna, Dept Internal Med III, Div Gastroenterol & Hepatol, Hans Popper Lab Mol Hepatol, Vienna, Austria

[7] Pomeranian Med Univ, Dept Med Biol, Szczecin, Poland

[8] Med Univ Warsaw, Dept Gen Transplant & Liver Surg, Liver & Internal Med Unit, Warsaw, Poland

[9] Univ Basque Country UPV EHU, Donostia Univ Hosp, Biodonostia Hlth Res Inst, Dept Liver & Gastrointestinal Dis,CIBERehd,Ikerba, Donostia San Sebastian, Spain

[10] Norfolk & Norwich Univ Hosp, Dept Gastroenterol, Norwich, Norfolk, England

来源：

HEPATOLOGY | 2019年 / 69卷 / 02期

基金：

英国生物技术与生命科学研究理事会;

关键词：

FARNESOID X RECEPTOR; BILE-ACID METABOLISM; NORURSODEOXYCHOLIC ACID; SCLEROSING CHOLANGITIS; URSODEOXYCHOLIC ACID; OBETICHOLIC ACID; GROWTH-FACTOR; FXR; PROLIFERATION; PATHOGENESIS;

D O I：

10.1002/hep.30275

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：699 / 716

页数：18

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