ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis
ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis
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DOI：
10.1136/gutjnl-2016-312485
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发表时间：
2018-04-01
期刊：
影响因子：
24.5
通讯作者：
Hellerbrand, Claus
中科院分区：
文献类型：
--
作者：
Mahli, Abdo;Saugspier, Michael;Hellerbrand, Claus
目的 伊立替康术前化疗与脂肪性肝炎的发生有关，从而增加肝脏手术围手术期发病率和死亡率的风险。这种化疗并发症的分子机制尚不清楚。 设计 在体外原代人肝细胞、伊立替康治疗的小鼠中以及伊立替康治疗的肝脏标本中与对照患者进行比较，研究了伊立替康诱导的脂肪性肝炎的机制。结果 伊立替康剂量依赖性诱导肝细胞中的脂质积累和促炎基因表达。伴随着线粒体功能受损，肉毒碱棕榈酰转移酶 I 表达减少，酰基辅酶 A 氧化酶-1 (ACOX1) 诱导、氧化应激和细胞外信号调节激酶 (ERK) 激活。 ERK 抑制可阻止伊立替康诱导的促炎基因表达，但对脂质积累只有轻微影响。然而，伊立替康还诱导溶酶体 pH 碱化介导的自噬通量受损。溶酶体 pH 值的重新酸化消除了伊立替康诱导的自噬损伤和脂质积累。同样在小鼠中，伊立替康治疗诱导肝脏 ACOX1 表达、ERK 磷酸化和炎症，以及自噬受损和明显的脂肪变性。此外，接受伊立替康治疗的患者显示出较高的肝脏 ERK 活性、促炎基因和标志物的表达，表明向过氧化物酶体脂肪酸氧化的转变和自噬通量受损。用多酪氨酸激酶抑制剂索拉非尼预处理不会影响自噬损伤和脂肪变性，但显着降低伊立替康处理的肝细胞和小鼠肝脏中的ERK磷酸化和炎症反应。结论伊立替康通过自噬损伤诱导肝脂肪变性，并通过ERK激活诱导炎症。索拉非尼似乎是预防和治疗伊立替康引起的炎症的一种新的治疗选择。
Objective Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown.Design Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients.Results Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acylcoenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers.Conclusions Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.