PO.CL11.01 · 临床研究

小鼠早期天冬酰胺酶肝毒性中的代谢和脂质组学变化

Metabolic and lipidomic changes in early asparaginase hepatotoxicity in mice

编号 5215 展板 6 时间 4/21 09:00–12:00 区域 Section 41 主讲 Steven Mittelman, MD;PhD

分会场 Biological and Clinical Consequences of Cancer Therapy

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作者与单位 Authors & Affiliations

Veronica Ruiz-Torres¹, Jennifer J. Chia², Michael D. Cohen³, Jia Tan³, Kevin J. Williams⁴, Nedas Matulionis⁴, Abby Krall⁴, Heather R. Christofk⁵, Etan Orgel⁶, Steven D. Mittelman⁷

¹UCLA Mattel Children's Hospital and Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández (UMH), Los Angeles, CA,²Department of Pathology and Laboratory Medicine, UCLA and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, Los Angeles, CA,³UCLA - University of California Los Angeles, Los Angeles, CA,⁴UCLA, Los Angeles, CA,⁵UCLA David Geffen School of Medicine, Los Angeles, CA,⁶Pediatric Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA,⁷UCLA Mattel Childrens Hospital, Los Angeles, CA

摘要 Abstract

中文摘要

天冬酰胺酶（ASNase）是治疗儿童急性淋巴细胞白血病的有效药物，但其应用受肝毒性限制，尤其是在肥胖患者中。虽然已证明ASNase可诱导脂肪细胞脂解和肝细胞整合应激反应，但ASNase导致肝脂肪变性和肝毒性的机制仍不清楚。我们此前研究了PEG-ASNase注射七天后对小鼠肝脏的影响。然而，到此时间点，肝脏已呈严重脂肪变性。因此，为揭示ASNase的早期效应，我们对18周龄肥胖和对照雄性C57Bl6小鼠给予单次腹腔注射3,000 IU/kg聚乙二醇化ASNase，并在三天后分析肝脏。ASNase在注射后仅3天就引起显著的肝脂肪变性（n=6；见表）。ASNase增加肝脏不饱和甘油三酯，降低磷脂酰胆碱和溶血磷脂酰胆碱。代谢组学发现s-腺苷甲硫氨酸（SAM）、5-氨基咪唑-4-甲酰胺核苷（AICAR）以及谷胱甘肽与谷胱甘肽二硫化物比值（GSH:GSSG，见表）降低，提示氧化应激。这些脂质组学和代谢组学变化在肥胖小鼠中更为明显。RNAseq发现ASNase后含patatin样磷脂酶结构域蛋白3（PNPLA3）表达降低（log2倍数变化为-4.8至-5.1，p<0.001）。qPCR显示与对照溶媒肝脏相比，肥胖肝脏中PNPLA3表达较低（p<0.001），并证实两组在ASNase后均出现显著抑制（见表）。我们的结果表明，在三天内，ASNase即可诱导肝脂肪变性、氧化应激、磷脂酰胆碱水平降低以及PNPLA3表达抑制。这些效应在肥胖状态下似乎被放大。由于磷脂酰胆碱和PNPLA3已知与代谢功能障碍相关性脂肪性肝病（MASLD）相关，这些效应很可能是ASNase肝毒性的促成因素。要完全理解这些变化的机制还需进一步研究。ASNase治疗后的肝脏变化：瘦体VEH、瘦体PEG、p值、肥胖VEH、肥胖PEG、p值。脂肪变性评分 0±0、2.833±0.477、0.002、2.667±0.333、3.833±0.401、0.050。GSH:GSSG（标准化）1.000±0.071、0.546±0.049、0.001、0.404±0.060、0.662±0.038、0.006。PNPLA3（RQ）1.234±0.771、0.016±0.007、0.011、0.026±0.009、0.005±0.002、0.072。

查看英文原文 English abstract

Asparaginase (ASNase) is an effective treatment for pediatric acute lymphoblastic leukemia but is limited by hepatotoxicity, particularly in obese patients. While ASNase has been shown to induce adipocyte lipolysis and hepatocyte integrated stress response, the mechanisms by which ASNase causes hepatosteatosis and hepatotoxicity remain unclear. We previously examined the effects of PEG-ASNase on livers in mice seven days after injection. However, by this timepoint, livers were severely steatotic. Therefore, to uncover early effects of ASNase, we treated obese and control 18-week-old male C57Bl6 mice with one IP dose of 3,000 IU/kg pegylated‑ASNase and analyzed livers three days later. ASNase caused significant hepatosteatosis already 3 days after injection (n=6; Table). ASNase increased liver unsaturated triglycerides and decreased phosphatidylcholine and lysophosphatidylcholine. Metabolomics identified decreases in s-adenylmethionine (SAM), 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), and glutathione to glutathione disulfide ratio (GSH:GSSG, Table), indicating oxidative stress. These lipidomic and metabolomic changes were more pronounced in obese mice. RNAseq identified lower expression of palatin-like phospholipase domain containing protein 3 (PNPLA3) after ASNase (-4.8 to -5.1 log 2 fold change, p<0.001). qPCR showed low PNPLA3 expression in obese compared to control vehicle livers (p<0.001) and confirmed substantial suppression after ASNase in both groups (Table). Our results show that within three days, ASNase induces hepatic steatosis, oxidative stress lower phosphatidylcholine levels and suppression of PNPLA3 expression. These effects appear to be magnified in obesity. Since phosphatidylcholine and PNPLA3 are known to be related to metabolic dysfunction associated steatotic liver disease (MASLD), these effects are likely contributory to ASNase hepatotoxicity. Further work is needed to fully understand the mechanisms of these changes. Liver changes with ASNase treatment Lean VEH Lean PEG p value Obese VEH Obese PEG p value Steatosis Score 0±0 2.833±0.477 0.002 2.667±0.333 3.833±0.401 0.050 GSH:GSSG (normalized) 1.000±0.071 0.546±0.049 0.001 0.404±0.060 0.662±0.038 0.006 PNPLA3 (RQ) 1.234±0.771 0.016±0.007 0.011 0.026±0.009 0.005±0.002 0.072

利益披露 Disclosure

K. J. Williams, None.. N. Matulionis, None.. A. Krall, None. E. Orgel, Jazz Pharmaceuticals Independent Contractor. S. D. Mittelman, Sanofi Independent Contractor.

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