Hepatic SIRT6 protects against cholestatic liver disease primarily via inhibiting bile acid synthesis
Wen Zhang1
Jiahui Wang1
Luyao Yang1
Yuyun Shao2
Hongjun Peng3
Longfeng Jiang4
Liang Sheng1
1.Department of Pharmacology,School of Basic Medical Sciences,Nanjing Medical University,Nanjing,Jiangsu 211166,China2.Endoscopy Center,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China3.Department of Pediatrics,Nanjing Drum Tower Hospital,Clinical College of Nanjing Medical University,Nanjing,Jiangsu 210008,China4.Department of Infectious Diseases,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China
摘要：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.
机标关键词：sirt6acidagainstbilecholestaticdiseasehepaticinhibiting
分类号：R575.7(消化系及腹部疾病)
论文发表日期：2025-07-30
在线出版日期：2025-10-11（本平台首次上网日期，不代表文献的发表时间）
页数：16( 340-355 )
英文信息