Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice.
Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice.
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DOI：
10.1016/j.apsb.2021.11.022
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Fernandez CA
中科院分区：
文献类型：
--
作者：
Kumar GVN;Hoshitsuki K;Rathod S;Ramsey MJ;Kokai L;Kershaw EE;Xie W;Fernandez CA
聚乙二醇化天冬酰胺酶（PEG-ASNase）是一种用于治疗小儿急性淋巴细胞白血病（ALL）的化疗药物。由于其肝损伤（包括肝脂肪变性）的高风险，成年人应避免使用它，肥胖和老年被认为是损伤的危险因素。本研究旨在阐明PEG-ASNase诱导肝损伤的机制。小鼠接受1500 U/kg PEG-ASNase，并在给药后1、3、5和7天处死。定量肝脏甘油三酯，并测量血浆胆红素、ALT、AST和非酯化脂肪酸（NEFA）。测定参与肝脂肪酸合成、β-氧化、极低密度脂蛋白（VLDL）分泌和白色脂肪组织（WAT）脂解的基因的mRNA和蛋白水平。小鼠在PEG-ASNase后发生肝脂肪变性，与胆红素、ALT和AST升高相关。在PEG-ASNase作用后，肝脏基因Ppara、Lcad/Mcad、Hadhb、Apob 100和Mttp上调，Srebp-1c和Fas下调。PEG-ASNase后还观察到血浆NEFA、WAT损失和脂肪组织脂解增加。此外，我们发现PEG-ASNase诱导的肝损伤在肥胖和老年小鼠中加重，与ASNase诱导的肝损伤的临床研究一致。我们的数据表明，PEG-ASNase诱导的肝损伤是由于药物诱导的脂解和脂质重新分配到肝脏。PEG-ASNase诱导的肝损伤在肥胖和老年小鼠中加重，与ASNase诱导的肝损伤的临床研究一致。这项研究表明，PEG-ASNase诱导的肝损伤是由于药物诱导的脂解和脂质重新分布到肝脏。
PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver. PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. This study suggests that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.
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