SIRT1激动剂CAY10602对急性肝衰竭小鼠肝损伤保护作用研究*

doi:10.3969/j.issn.1672-5069.2025.01.006

摘要/Abstract

摘要： 目的探讨沉默信息调控因子2相关酶1(SIRT1)激动剂CAY10602对急性肝衰竭(ALF)小鼠肝脏的保护作用。方法将40只小鼠随机分为对照组、LPS/D-Gal模型组、LPS/D-Gal/CAY10602处理组、LPS/D-Gal/GLY处理组和LPS/D-Gal/CAY10602/GLY处理组,每组8只。采用腹腔注射脂多糖联合D-氨基半乳糖(LPS/D-Gal)方法制备ALF小鼠模型,分别给予SIRT1激动剂CAY10602和高迁移率族蛋白B1(HMGB1)抑制剂甘草酸(GLY)干预。采用Western blot法检测小鼠肝组织SIRT1、HMGB1以及铁死亡相关蛋白谷胱甘肽过氧化物酶4(GPX4)和酰基辅酶A合成酶长链家族成员4(ACSL4)表达。结果 LPS/D-Gal模型组小鼠肝组织结构严重紊乱,肝细胞大片坏死,肝组织淤血严重,制备模型成功,而SIRT1激动剂CAY10602能够显著减轻ALF小鼠肝组织损伤;LPS/D-Gal模型组小鼠血清ALT、AST和TBIL水平分别为(3278.3±520.8)U/L、(2457.0±545.5)U/L和(96.4±16.5)μmol/L,显著高于对照组[分别为(32.1±10.3)U/L、(67.8±12.8)U/L和(4.7±2.3)μmol /L,P < 0.05],LPS/D-Gal/CAY10602组小鼠血清ALT、AST和TBIL水平分别为(1438.2±259.8)U/L、(944.1±112.8)U/L和(54.4±10.8)μmol /L,显著低于模型组(P < 0.05);Western blot检测结果显示,与模型组比,CAY10602显著降低了HMGB1表达(P <0.05),促进了铁死亡相关蛋白GPX4表达,降低了ACSL4表达(P<0.05),表明SIRT1激动剂CAY10602可能通过降低HMGB1以及肝组织铁死亡蛋白表达进而减轻肝组织的损伤。结论 SIRT1激动剂CAY10602能够减轻ALF小鼠肝组织损伤,对肝脏具有保护作用,其作用机制可能是抑制了HMGB1的释放和抑制肝组织铁死亡的发生。

关键词: 急性肝衰竭, 沉默信息调控因子2相关酶1, 高迁移率族蛋白B1, 铁死亡, 小鼠

Abstract: Objective This experiment was performed to investigate protective effects of silencing information regulator 2 related enzyme 1 (SIRT1) agonist CAY10602 on liver injuries in mice with acute liver failure (ALF). Methods Forty mice were randomly divided into 5 groups, e.g., control, model, CAY10602-intervend, glycyrrhizin (GLY)-intervened and CAY10602 and GLY combination-intervened group, with 8 mice in each group. A model of ALF was established by intraperitoneal injection of lipopolysaccharide and D-galactosamine (LPS/D-Gal). SIRT1 agonist CAY10602 and high mobility group box-1 protein (HMGB1) inhibitor glycyrrhizin (GLY) were used for intervention. Hepatic expression of SIRT1, HMGB1, and ferroptosis-related protein glutathione peroxidase 4 (GPX4), and Acyl-CoA synthetase long-chain family member 4 (ACSL4) was detected by Western blot. Results Liver tissue structure of mice in LPS/D-Gal model group was seriously disordered, necrosis of hepatocytes was found, and liver tissue congestion was serious; However, SIRT1 agonist CAY10602 intervention could significantly ameliorate liver tissue injuries; serum ALT, AST and bilirubin levels in LPS/D-Gal model group mice were (3278.3±520.8) U/L, (2457.0±545.5) U/L and (96.4±16.5) μmol/L, significantly higher than in control group [(32.1±10.3) U/L, (67.8±12.8) U/L and (4.7±2.3) μmol/L, P<0.05]; serum ALT, AST and bilirubin levels in LPS-Gal/D/CAY10602-intervened group mice were significantly lower than in the model group; compared with in the model group, CAY10602 significantly decreased hepatic expression of HMGB1 (P <0.05), while promoted ferroptosis-related protein GPX4 expression, and decreased expression of ACSL4 (P<0.05), suggesting that SIRT1 agonist CAY10602 might alleviate liver injuries by inhibiting HMGB1 expression and reducing ferroptosis in liver tissues. Conclusions SIRT1 agonist CAY10602 can protect liver tissue injuries, and the mechanism might be involved inhibition of hepatic HMGB1 release and ferroptosis occurrence.

Key words: Acute liver failure, Silencing information regulator 2 related enzyme 1, High mobility group box-1 protein, Ferroptosis, Mice

沈起艳, 张龙, 张艳琼, 张小雅, 王鲁文, 龚作炯. SIRT1激动剂CAY10602对急性肝衰竭小鼠肝损伤保护作用研究^*[J]. 实用肝脏病杂志, 2025, 28(1): 20-23.

Shen Qiyan, Zhang Long, Zhang Yanqiong, et al. Protection of CAY10602, a SIRT1 agonist, on liver injuries in mice with LPS/D-Gal-induced acute liver failure[J]. Journal of Practical Hepatology, 2025, 28(1): 20-23.

参考文献

[1] Ambrocio GPL, Aguado S, Carrillo J, et al. Hepatitis E virus infection in lung transplant recipients: A case series. Transplant Proc, 2019, 51(2): 376-379.
[2] Axley P, Ahmed Z, Arora S, et al. NASH is the most rapidly growing etiology for acute-on-chronic liver failure-related hospitalization and disease burden in the United States: a population-based study. Liver Transpl, 2019, 25(5): 695-705.
[3] 仁增卓嘎,王志鑫,尹凤娇,等. 抗菌肽抑制Caspase－3表达对内毒素诱导的急性肝衰竭小鼠肝细胞凋亡的影响. 实用肝脏病杂志,2023,26(4):472-475.
[4] Wilking MJ, Singh CK, Nihal M, et al. Sirtuin deacetylases: a new target for melanoma management. Cell Cycle, 2014, 13(18): 2821-2826.
[5] Ong ALC, Ramasamy TS. Role of sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Res Rev, 2018, 43: 64-80.
[6] Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res, 2009, 69(5): 1702-1705.
[7] Wei S, Gao Y, Dai X, et al. SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury. Am J Physiol Renal Physiol, 2019, 316(1): F20-F31.
[8] Chen X, Liu Q, Wu E, et al. The role of HMGB1 in digestive cancer. Biomed Pharmacother, 2023, 167: 115575.
[9] Wang Y, Chen Q, Jiao F, et al. Histone deacetylase 2 regulates ULK1 mediated pyroptosis during acute liver failure by the K68 acetylation site. Cell Death Dis, 2021, 12(1): 55.
[10] Jiao F, Wang Y, Chen Q, et al. Role of SIRT1 in hepatic encephalopathy: in vivo and in vitro studies focusing on the NLRP3 inflammasome. Oxid Med Cell Longev, 2021, 2021: 5522708.
[11] Wang Y, Chen Q, Shi C, et al. Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress. Mol Med Rep, 2019, 20(5): 4081-4090.
[12] Reuben A, Tillman H, Fontana RJ, et al. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med, 2016, 164(11): 724-732.
[13] De Gregorio E, Colell A, Morales A, et al. Relevance of SIRT1-NF-kappa B axis as therapeutic target to ameliorate inflammation in liver disease. Int J Mol Sci, 2020, 21(11):3858.
[14] Yin H, Hu M, Liang X, et al. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology, 2014, 146(3): 801-811.
[15] Pfluger PT, Herranz D, Velasco-miguel S, et al. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A, 2008, 105(28): 9793-9798.
[16] Lu B, Antoine DJ, Kwan K, et al. JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc Natl Acad Sci U S A, 2014, 111(8): 3068-3073.
[17] Yang H, Hreggvidsdottir HS, Palmblad K, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A, 2010, 107(26): 11942-11947.
[18] Khambu B, Yan S, Huda N, et al. Role of high-mobility group box-1 in liver pathogenesis. Int J Mol Sci, 2019, 20(21):5314.
[19] Sappington PL, Yang R, Yang H, et al. HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology, 2002, 123(3): 790-802.
[20] Zhang W, Gong M, Zhang W, et al. Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling. Cell Death Dis, 2022, 13(7): 630.
[21] Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ, 2019, 26(11): 2284-2299.
[22] Cheng J, Fan YQ, Liu B H, et al. ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncol Rep, 2020, 43(1): 147-158.

SIRT1激动剂CAY10602对急性肝衰竭小鼠肝损伤保护作用研究^*

Protection of CAY10602, a SIRT1 agonist, on liver injuries in mice with LPS/D-Gal-induced acute liver failure

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