目的: 受肝纤维化影响的人群广泛,而治疗方法缺乏。沉默信息调节因子2相关酶类7（silencing information regulator 2 related enzyme,SIRT7）是组蛋白去乙酰化酶sirtuin家族的成员,参与细胞衰老、代谢和炎症反应等多种生理学过程。据报道,SIRT7在许多肝脏疾病如肝癌和脂肪性肝炎中发挥重要作用,本研究旨在探究SIRT7在肝纤维化中的功能。方法: 通过四氯化碳（CCl4）隔天腹腔注射,在野生型小鼠和肝细胞SIRT7特异性敲除小鼠中建立肝纤维化模型并进行损伤与纤维化表型测定。采用原代细胞分离与纯化技术进行体外共培养实验,结合阵列图进一步分析确定SIRT7缺失影响肝星状细胞（hepatic stellate cells,HSC）激活的分子媒介。结果: SIRT7缺失加剧了CCl4诱导的肝损伤和纤维化表型。进一步研究表明,SIRT7缺失介导肝细胞PAI-1分泌差异激活HSC从而促进肝纤维化。结论: SIRT7介导的信号在肝损伤和纤维化中发挥重要作用,靶向SIRT7可能是治疗肝纤维化的有效途径。
Abstract
Background The population affected by liver fibrosis is extensive, yet treatment options are lacking. SIRT7, a member of the sirtuin family of histone deacetylases, is involved in various physiological processes such as cellular aging, metabolism, and inflammatory responses. It has been reported that SIRT7 plays crucial roles in many liver diseases, including hepatocellular carcinoma and non-alcoholic fatty liver disease, but its function in liver fibrosis remains unclear. Methods A liver fibrosis model was established by alternate-day intraperitoneal injection of CCl4 in both wild-type mice and hepatocyte SIRT7 knockout mice, followed by assessment of injury and fibrosis phenotypes. Subsequently, primary cells were used for in vitro co-culture experiments, combined with array analysis to further determine the mediators of hepatic stellate cell (HSC) activation affected by SIRT7 deficiency. Conclusion SIRT7 deficiency exacerbated CCl4-induced liver injury and fibrosis phenotypes. Further research indicated that SIRT7 deficiency mediated differential activation of hepatic stellate cells (HSCs) through hepatocyte PAI-1 secretion, thereby promoting liver fibrosis. Our results suggested that SIRT7-mediated signaling plays a significant role in liver injury and fibrosis, and therapeutic targeting SIRT7 may be an effective approach for treating liver fibrosis.
关键词
肝纤维化 /
SIRT7 /
肝星状细胞 /
旁分泌
Key words
epigenetic factor /
liver fibrosis /
hepatic stellate cells /
paracrine secretion
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参考文献
[1] LEE Y A, WALLACE M C, FRIEDMAN S L.Pathobiology of liver fibrosis: a translational success story[J]. Gut, 2015, 64(5) : 830-841.
[2] BATALLER R, BRENNER D A.Liver fibrosis[J]. J Clin Invest, 2005, 115(2) : 209-218.
[3] TROEGER J S, MEDERACKE I, GWAK G-Y, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice [J]. Gastroenterology, 2012, 143 (4): 1073-10832. e22 .
[4] LO R C, KIM H.Histopathological evaluation of liver fibrosis and cirrhosis regression[J]. Clin Mol Hepatol, 2017, 23(4) : 302-307.
[5] PELLICORO A, RAMACHANDRAN P, IREDALE J P, et al.Liver fibrosis and repair: immune regulation of wound healing in a solid organ[J]. Nat Rev Immunol, 2014, 14(3) : 181-194.
[6] TACKE F.Targeting hepatic macrophages to treat liver diseases[J]. J Hepatol, 2017, 66(6) : 1300-1312.
[7] KRENKEL O, TACKE F.Liver macrophages in tissue homeostasis and disease[J]. Nat Rev Immunol, 2017, 17(5) : 306-321.
[8] HIGASHI T, FRIEDMAN S L, HOSHIDA Y.Hepatic stellate cells as key target in liver fibrosis[J]. Adv Drug Deliv Rev, 2017, 121: 27-42.
[9] LI G, TANG X, ZHANG S, et al.SIRT7 activates quiescent hair follicle stem cells to ensure hair growth in mice[J]. EMBO J, 2020, 39(18) : e104365.
[10] YOSHIZAWA T, KARIM M F, SATO Y, et al.SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway[J]. Cell Metab, 2014, 19(4) : 712-721.
[11] WINNIK S, AUWERX J, SINCLAIR D A, et al.Protective effects of sirtuins in cardiovascular diseases: from bench to bedside[J]. Eur Heart J, 2015, 36(48) : 3404-3012.
[12] KUMARI P, TARIGHI S, BRAUN T, et al.SIRT7 Acts as a Guardian of Cellular Integrity by Controlling Nucleolar and Extra-Nucleolar Functions[J]. Genes (Basel) , 2021, 12(9): 1361 .
[13] BLANK M F, GRUMMT I.The seven faces of SIRT7[J]. Transcription, 2017, 8(2) : 67-74.
[14] SHIN J, HE M, LIU Y, et al.SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease[J]. Cell Rep, 2013, 5(3) : 654-665.
[15] YANAI M, KURATA M, MUTO Y, et al.Clinicopathological and molecular analysis of SIRT7 in hepatocellular carcinoma[J]. Pathology, 2020, 52(5) : 529-537.
[16] GäBELE E, BRENNER D A, RIPPE R A. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell[J]. Front Biosci, 2003, 8: d69-d77.
[17] MILANI S, HERBST H, SCHUPPAN D, et al.Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis[J]. Gastroenterology, 1990, 98(1) : 175-184.
[18] MARRA F.Hepatic stellate cells and the regulation of liver inflammation[J]. J Hepatol, 1999, 31(6) : 1120-1130.
[19] PUCHE J E, SAIMAN Y, FRIEDMAN S L.Hepatic stellate cells and liver fibrosis[J]. Compr Physiol, 2013, 3(4) : 1473-1492.
[20] DING N, YU R T, SUBRAMANIAM N, et al.A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response[J]. Cell, 2013, 153(3) : 601-613.
[21] KMIEĆ Z.Cooperation of liver cells in health and disease[J]. Adv Anat Embryol Cell Biol, 2001, 161: 1-151.
[22] CANBAY A, FRIEDMAN S, GORES G J.Apoptosis: the nexus of liver injury and fibrosis[J]. Hepatology, 2004, 39(2) : 273-278.
[23] GUO R, JIA X, DING Z, et al.Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation[J]. Theranostics, 2022, 12(11) : 5220-5236.
[24] ZHOU X, XIE Y, XIAO H, et al.MicroRNA-519d inhibits proliferation and induces apoptosis of human hypertrophic scar fibroblasts through targeting Sirtuin 7[J]. Biomed Pharmacother, 2018, 100: 184-190.
基金
国家自然科学基金面上项目“基于单细胞测序技术的ALD相关肝巨噬细胞亚群动态监测与功能研究”（82170607）; 湖南省自然科学基金杰出青年基金“免疫微环境与酒精性肝病”（2022JJ10037）; 湖南省大学生研究性学习和创新性实验计划项目“化疗药物奥沙利铂介导的氧化应激诱导肝损伤机制与治疗研究”（S202310542190）
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