Role of SIRT6 in progression of liver fibrosis and its mechanism
10.3969/j.issn.1000-4718.2024.09.011
- VernacularTitle:SIRT6在肝纤维化形成进程中的作用及其机制
- Author:
Xiaping LIN
1
;
Xianyu HUANG
;
Jian SUN
;
Yingying LI
;
Yunyan XU
;
Bo HUANG
;
Yuan YANG
;
Qin WU
Author Information
1. 遵义医科大学基础药理教育部重点实验室暨特色民族药教育部国际合作联合实验室,贵州 遵义 563006
- Keywords:
liver fibrosis;
carbon tetrachloride;
hepatic stellate cells;
silent information regulator 6;
inflam-matory factors
- From:
Chinese Journal of Pathophysiology
2024;40(9):1652-1659
- CountryChina
- Language:Chinese
-
Abstract:
AIM:This study aims to investigate the effects and mechanisms of silent information regulator 6(SIRT6)on carbon tetrachloride(CCl4)-induced liver fibrosis in mice,as well as the expression changes in the down-stream pathways of hepatic stellate cells after SIRT6 silencing.METHODS:Thirty male C57BL/6J mice were randomly divided into a normal control group(n=6)and a model group(modeling at 2,4,8,12 weeks,n=24).A liver fibrosis model in mice was prepared by intraperitoneal injection of CCl4 twice a week for 12 weeks.Serum alanine aminotransfer-ase(ALT)and aspartate aminotransferase(AST)levels were measured to assess liver injury.Hematoxylin-eosin(HE)and Masson staining were used to observe the pathological changes in mouse liver tissues.Immunohistochemical staining was conducted to detect the expression of α-smooth muscle actin(α-SMA)in the liver,Western blot analysis was used to measure the expression of liver α-SMA,SIRT6,acetyl histone H3 at Lys9(H3K9ac),acetyl histone H3 at Lys56(H3K56ac),interleukin-1β(IL-1β),and IL-18 proteins.Hepatic stellate cells-T6(HSC-T6)underwent SIRT6 gene si-lencing,divided into NC siRNA group and SIRT6 siRNA group,with Western blot performed to detect the expression of SIRT6,H3K9ac,and H3K56ac proteins.RESULTS:Compared with the normal control group,the serum ALT and AST levels in the model group were significantly increased(P<0.05);HE and Masson staining results showed that the patho-logical changes in the liver of the model group worsened over time,with an increase in collagen fiber deposition.Both im-munohistochemistry and Western blot showed that the expression of liver α-SMA significantly increased at 8 and 12 weeks in the model group(P<0.05).Western blot results showed that the expression of SIRT6 protein in the liver of all model group mice was lower than that in the normal control group(P<0.05),and decreased gradually with the progression of liv-er fibrosis;also,the expression levels of H3K9ac,H3K56ac,IL-1β,and IL-18 in the liver of the model group mice were significantly elevated at 8 and 12 weeks(P<0.05);after SIRT6 silencing,compared with the NC siRNA group,the levels of H3K9ac and H3K56ac in the SIRT6 siRNA group significantly increased(P<0.05).CONCLUSION:The deficiency of SIRT6,by abnormally increasing H3K9ac and H3K56ac,raises the expression of IL-1β and IL-18,intensifying the in-flammatory response and promoting the progression of liver fibrosis,indicating that the aberrant expression of SIRT6 is in-volved in the development of liver fibrosis.
