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 acyl-coenzyme 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.

中文翻译：

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ERK 激活和自噬损伤是伊立替康诱导的脂肪性肝炎的中枢介质

目的 术前伊立替康化疗与脂肪性肝炎的发生有关，增加了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广为人知。设计 在体外原代人肝细胞、伊立替康治疗的小鼠和伊立替康治疗的肝脏标本中，与对照患者相比，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地诱导肝细胞中的脂质积累和促炎基因表达。这伴随着线粒体功能受损，肉碱棕榈酰转移酶 I 的表达降低和酰基辅酶 A 氧化酶-1 (ACOX1) 的诱导，氧化应激和细胞外信号调节激酶 (ERK) 激活。ERK 抑制阻止了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，伊立替康也诱导溶酶体 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，以及自噬受损和显着脂肪变性。此外，伊立替康治疗的患者表现出更高的肝脏 ERK 活性、促炎基因的表达和指示向过氧化物酶体脂肪酸氧化转变和自噬通量受损的标志物。多酪氨酸激酶抑制剂索拉非尼预处理不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，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型治疗选择。