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  • Title: SIRT7 affects autophagy and activation of hepatic stellate cells by regulating the acetylation level of high mobility group protein 1.
    Author: Xiao ZH, Xie ZY, Wang Q, Lu H, Cao HW.
    Journal: Immunobiology; 2023 Mar; 228(2):152323. PubMed ID: 36753789.
    Abstract:
    OBJECTIVE: Preventing the progression of hepatic fibrosis is an important strategy to improve the prognosis of liver disease. The purpose of this study was to investigate the role of sirtuin7 (SIRT7) and high mobility group box 1 (HMGB1) acetylation in the occurrence and development of hepatic fibrosis. MATERIALS AND METHODS: Hepatic fibrosis mice model was induced by CCl4. TGF-β1 was used to activated quiescent hepatic stellate cell (qHSC) into activated HSC (aHSC). Hematoxylin-eosin evaluated hepatic fibrosis in vivo, and the distribution of α-smooth muscle actin (α-SMA) or HMGB1 was detected by immunohistochemistry or immunofluorescence. The expressions of SIRT7, autophagy related proteins, and HSC activation-related proteins were detected by Western blot. Immunoprecipitation detected the acetylation level of HMGB1. Lysine mutants of HMGB1 were constructed in vitro to explore the acetylation sites of HMGB1. RESULTS: Hepatocyte autophagy and activation levels were enhanced in CCl4 group or aHSC group, and the acetylation level of HMGB1 was increased. Nuclear transfer of HMGB1 occurred in aHSC, and HMGB1was mainly distributed in cytoplasm. The expression of SIRT7 in CCl4 group or aHSC group was most significantly decreased, and knockdown of SIRT7 leads to increased levels of HSCs autophagy and activation. Overexpression of SIRT7 or interference of HMGB1 alone in aHSC can reduce the level of autophagy and activation of aHSC. However, continued overexpression of SIRT7 in shHMGB1-aHSC could not reduce the autophagy and activation levels of aHSC. Among the 11 Flag-HMGB1 mutants, the acetylation level of K86R-Flag-HMGB1 was the lowest. The acetylation level of K86R-Flag-HMGB1 did not change due to SIRT7 downregulation. CONCLUSION: This study proved that SIRT7 can directly target the K86R site of HMGB1 and participate in regulating the expression and distribution of HMGB1, thus affecting the autophagy and activation level of HSCs.
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