Hepatic SIRT6 protects against cholestatic liver disease primarily via inhibiting bile acid synthesis
Wen Zhang
Jiahui Wang
Luyao Yang
Yuyun Shao
Hongjun Peng
Longfeng Jiang
Liang Sheng
Abstract：Cholestatic liver disease, caused by the accumulation of hazardous bile acids in the liver, may result in cirrhosis, fibrosis, or liver failure. Activation of sirtuin 6 (SIRT6) prevents cholestasis-associated pathological events, such as oxidative stress and mitochondrial biogenesis dysfunction, and inhibits bile acid synthesis to alleviate cholestatic liver injury. However, it remains uncertain which pathway mediates the therapeutic effect of SIRT6 in reducing cholestasis. Therefore, we treated liver-specific Sirt6 knockout mice with N-acetylcysteine, KEAP1-NRF2-IN-1, or acadesine to alleviate oxidative stress and/or promote mitochondrial biogenesis after modeling cholestatic liver disease, but these measures did not significantly improve cholestatic symptoms. However, MDL801, a SIRT6 agonist that downregulates cholesterol 7α-hydroxylase (CYP7A1, the key enzyme in bile acid synthesis) levels, exhibited favorable therapeutic effects. Additionally, the hepatic knockdown of Cyp7a1 further demonstrated that inhibiting hepatic bile acid synthesis might be the main pathway through which SIRT6 alleviates cholestatic liver disease. These findings provide a solid basis for the potential application of SIRT6 agonists in treating cholestatic liver disease.
Keywords：sirtuin 6cholestatic liver diseaseoxidative stressmitochondrial biogenesisbile acid synthesis
Publication Date：2025-07-30
Online Publishing Date：2025-10-11(First online date of this platform, not the publication date of the document)
Pages：16( 340-355 )