Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease.
Fine-Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease.
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SIRTUIN 1表达的微调对于保护肝脏免受胆固醇肝病至关重要。
DOI：
10.1002/hep.30275
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Beraza N
中科院分区：
文献类型：
--
作者：
Blokker BA;Maijo M;Echeandia M;Galduroz M;Patterson AM;Ten A;Philo M;Schungel R;Gutierrez-de Juan V;Halilbasic E;Fuchs C;Le Gall G;Milkiewicz M;Milkiewicz P;Banales JM;Rushbrook SM;Mato JM;Trauner M;Müller M;Martínez-Chantar ML;Varela-Rey M;Beraza N
胆汁淤积包括以胆汁酸在肝脏中积聚为特征的病因异质性病症，胆汁酸的积聚积极地促成肝损伤。SIRT 1通过调节法尼醇X受体（FXR）调节肝再生和胆汁酸代谢，我们在此研究其在胆汁淤积性肝病中的作用。我们测定了胆汁淤积性疾病患者肝脏中SIRT 1的表达，在两种实验性胆汁淤积模型中，以及在人类和小鼠肝细胞中对胆汁酸负荷的反应。对SIRT 1过表达（SIRToe）和肝细胞特异性SIRT 1-KO（敲除）小鼠（SIRThep-/-）进行胆管结扎（BDL），并喂食0.1% DDC（3，5-二乙氧羰基-1，4-二氢可力丁）饲料，以确定胆汁淤积期间SIRT 1的生物学相关性。在BDL/SIRToe小鼠中检测了NorUDCA（24-去甲熊去氧胆酸）的作用。我们发现SIRT 1在胆汁淤积患者、BDL后小鼠和Mdr 2敲除小鼠（Mdr 2-/-）动物的肝脏中高度表达。在体内和体外证实了SIRT 1在胆汁淤积期间的有害作用。SIRToe小鼠表现出加重的实质损伤，而SIRThep-/-小鼠在BDL和0.1%DDC喂养后表现出中度改善。同样地，从SIRToe小鼠分离的肝细胞显示响应于胆汁酸的凋亡增加，而在SIRThep-/-肝细胞中观察到显著减少。重要的是，norUDCA治疗引起的SIRT 1降低（但不是完全抑制）与BDL/SIRToe小鼠肝实质的显著改善相关。有趣的是，SIRT 1过表达和肝细胞特异性SIRT 1耗竭均与FXR抑制相关，而NorUDCA对SIRT 1的调节与FXR信号转导恢复相关。结论：SIRT 1在人和小鼠胆汁淤积过程中表达增加。SIRT 1的微调表达对于保护肝脏免受胆汁淤积性肝损伤至关重要。
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.
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影响因子：
13.5
作者：
Kulkarni, Supriya R.;Soroka, Carol J.;Hagey, Lee R.;Boyer, James L.
通讯作者：
Boyer, James L.
影响因子：
13.5
作者：
Garcia-Rodriguez, Juan L.;Barbier-Torres, Lucia;Fernandez-Alvarez, Sara;Gutierrez-de Juan, Virginia;Monte, Maria J.;Halilbasic, Emina;Herranz, Daniel;Alvarez, Luis;Aspichueta, Patricia;Marin, Jose J. G.;Trauner, Michael;Mato, Jose M.;Serrano, Manuel;Beraza, Naiara;Luz Martinez-Chantar, Maria
通讯作者：
Luz Martinez-Chantar, Maria
DOI：
10.1016/j.bbadis.2017.09.019
发表时间：
2018-04-01
影响因子：
6.2
作者：
Cariello, Marica;Piccinin, Elena;Moschetta, Antonio
通讯作者：
Moschetta, Antonio
影响因子：
29.4
作者：
Eaton JE;Talwalkar JA;Lazaridis KN;Gores GJ;Lindor KD
通讯作者：
Lindor KD
影响因子：
25.7
作者：
Castro, Rui E.;Ferreira, Duarte M. S.;Rodrigues, Cecilia M. P.
通讯作者：
Rodrigues, Cecilia M. P.