PO.CL11.01 · 临床研究

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

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

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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