SIRT7 deficiency in hepatic cell mediates PAI-1 secretion, activating hepatic stellate cell and promoting liver fibrosis

YU Tingzi; DING Cong; TANG Yongyi; LI Zhuan

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Journal of Hunan Normal University(Medical Science) ›› 2024, Vol. 21 ›› Issue (2) : 15-20.

SIRT7 deficiency in hepatic cell mediates PAI-1 secretion, activating hepatic stellate cell and promoting liver fibrosis

YU Tingzi, DING Cong, TANG Yongyi, LI Zhuan

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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.

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epigenetic factor / liver fibrosis / hepatic stellate cells / paracrine secretion

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YU Tingzi, DING Cong, TANG Yongyi, LI Zhuan. SIRT7 deficiency in hepatic cell mediates PAI-1 secretion, activating hepatic stellate cell and promoting liver fibrosis[J]. Journal of Hunan Normal University(Medical Science). 2024, 21(2): 15-20

References

[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.