Farnesyltransferase inhibitor, tipifarnib, prevents galactosamine/lipopolysaccharide-induced acute liver failure.
Farnesyltransferase inhibitor, tipifarnib, prevents galactosamine/lipopolysaccharide-induced acute liver failure.
复制标题
法尼基转移酶抑制剂替比法尼 (tipifarnib) 可预防半乳糖胺/脂多糖诱导的急性肝衰竭。
DOI：
10.1097/shk.0000000000000239
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Ichinose F
中科院分区：
文献类型：
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作者：
Shirozu K;Hirai S;Tanaka T;Hisaka S;Kaneki M;Ichinose F
急性肝功能衰竭（ALF）是一种与大量肝细胞死亡相关的致死性综合征。除了肝移植之外，ALF无法治愈。蛋白质法尼基化是由法尼基转移酶（FTase）催化的半胱氨酸残基的脂质修饰，并且已被提出为急性炎症的组成部分。以前，我们已经证明，FTase抑制剂改善内毒素血症和脓毒症小鼠模型的存活率。在这里，我们研究了FTase抑制剂替吡法尼对半乳糖胺（GalN）/脂多糖（LPS）诱导的急性肝衰竭的影响。在GalN（400 mg/kg，IP）和LPS（3 μg/kg）攻击的小鼠中通过组织学和生化分析研究替吡法尼（10 mg/kg，IP）的作用。GalN/LPS给药引起显著的肝损伤，其特征在于血浆丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平升高，导致小鼠显著死亡。Tipifarnib抑制GalN/LPS诱导的半胱天冬酶3激活，炎性细胞因子的产生，和c-Jun N-末端激酶（JNK）磷酸化的肝脏。另一方面，Tipifarnib上调GalN/LPS攻击后肝脏中的抗凋亡蛋白Bcl-xL。替吡法尼还通过抑制半胱天冬酶3激活和上调抗凋亡蛋白来保护原代肝细胞免受GalN/肿瘤坏死因子-α（TNF-α）诱导的细胞死亡。GalN/LPS诱导的肝损伤与肝脏中蛋白质法尼基化增加有关。Tipifarnib阻止了肝脏中的蛋白法尼基化，并显著减轻了GalN/LPS攻击小鼠的肝损伤和死亡率。这些结果表明，蛋白法尼基化是一个新的潜在的分子靶点，以防止肝细胞死亡和急性炎症性肝衰竭在暴发性肝炎。
Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. There is no cure for ALF except liver transplantation. Protein farnesylation is a lipid modification of cysteine residues that is catalyzed by farnesyltransferase (FTase) and has been proposed as an integral component of acute inflammation. Previously, we have demonstrated that FTase inhibitors improve survival in mouse models of endotoxemia and sepsis. Here we studied the effects of FTase inhibitor, tipifarnib, on galactosamine (GalN) /lipopolysaccharide (LPS)-induced acute liver failure. The effects of tipifarnib (10 mg/kg, IP) were studied in GalN (400 mg/kg, IP) and LPS (3 μg/kg)-challenged mice by histological and biochemical analyses. GalN/LPS administration caused prominent liver injury characterized by the increased plasma alanine aminotransferase (ALT) and aspartic aminotransferase (AST) levels leading to significant mortality in mice. Tipifarnib inhibited GalN/LPS-induced caspase 3 activation, inflammatory cytokine production, and c-Jun N-terminal Kinase (JNK) phosphorylation in the liver. On the other hand, Tipifarnib upregulated anti-apoptotic protein, Bcl-xL, in the liver after GalN/LPS challenge. Tipifarnib also protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death by inhibiting caspase 3 activation and upregulating anti-apoptotic proteins. GalN/LPS-induced liver injury was associated with increased protein farnesylation in the liver. Tipifarnib prevented protein farnesylation in the liver and markedly attenuated liver injury and mortality in GalN/LPS-challenged mice. These results suggest that protein farnesylation is a novel potential molecular target to prevent hepatocyte death and acute inflammatory liver failure in fulminant hepatitis.