Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure
Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure
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DOI：
10.1089/ars.2013.5354
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发表时间：
2014-01-10
影响因子：
6.6
通讯作者：
Ichinose, Fumito
中科院分区：
文献类型：
--
作者：
Shirozu, Kazuhiro;Tokuda, Kentaro;Ichinose, Fumito
目的：急性肝功能衰竭(ALF)是一种由大量肝细胞死亡引起的致命性综合征。硫化氢(H_2S)具有细胞保护或细胞毒性作用。在这里，我们研究了半乳糖胺(GalN)和脂多糖(LPS)诱导的ALF中产生硫化氢的半胱硫氨酸裂解酶(CSE)的作用。结果：野生型(WT)小鼠在GalN/LPS攻击后死亡率高，肝损伤明显，血浆丙氨酸氨基转移酶水平升高。L-丙叉甘氨酸对CSE的先天缺陷或化学抑制可减轻GalN/LPS诱导的肝损伤。CSE缺乏可显著提高小鼠的存活率，减轻GalN/LPS诱导的肝脏炎症细胞因子上调和caspase3及多聚ADP核糖聚合酶(PARP)的激活。CSE缺乏保护原代肝细胞免受GalN/肿瘤坏死因子(TNF)诱导的细胞死亡，但不影响内毒素诱导的原代腹膜巨噬细胞产生肿瘤坏死因子。CSE缺乏的有益影响与显著升高同型半胱氨酸和硫代硫酸盐水平，上调NF-E2P45相关因子2(Nrf2)和抗氧化蛋白，激活Akt依赖的抗凋亡信号，以及抑制GalN/LPS诱导的JNK磷酸化有关。最后，给予硫代硫酸钠(STS)可通过激活Akt和Nrf2依赖的信号转导通路和抑制GalN/LPS诱导的JNK磷酸化来减轻GalN/LPS诱导的WT小鼠肝损伤。创新：这些结果表明，抑制CSE或给予STS通过增加硫代硫酸盐水平和上调肝脏中的抗氧化剂和抗细胞凋亡防御来预防急性炎症性肝衰竭。结论：CSE的先天缺陷或化学抑制增加了肝脏中硫代硫酸盐的水平，并至少部分地通过增强抗氧化和抗凋亡机制来预防ALF。抗氧化剂。氧化还原信号。20,204-216。
Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine -lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor- (TNF-)-induced cell death without affecting LPS-induced TNF- production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms. Antioxid. Redox Signal. 20, 204-216.