Induction of Cyp2e1 contributes to asparaginase-induced hepatocyte sensitization to lipotoxicity  

作　　者：Yin Zhu Yuyin Wang Keito Hoshitsuki Da Yang Lauren Kokai Xiaochao Ma Wen Xie Christian A.Fernandez 

机构地区：[1]Center for Pharmacogenetics and Department of Pharmaceutical Sciences,University of Pittsburgh,Pittsburgh,PA 15261,USA [2]Department of Plastic Surgery,University of Pittsburgh and the McGowan Institute for Regenerative Medicine,Pittsburgh,PA 15261,USA

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期963-972,共10页药学学报(英文版)

基　　金：supported by the University of Pittsburgh School of Pharmacy and NIH Grants R01CA216815 and R01DK140079(USA).

摘　　要：One of the leading therapies for acute lymphoblastic leukemia(ALL)is the chemotherapeutic agent PEGylated E.coli-derived-l-asparaginase(PEG-ASNase).Due to the high risk of dose-limiting liver injury,characterized by clinically elevated levels of hepatic transaminases,PEG-ASNase therapy is generally avoided in adult patients.Our preclinical investigations have indicated that PEG-ASNase-induced liver injury is associated with the release of free fatty acids(FFAs)from white adipose tissue(WAT),suggesting potential lipotoxic effects.However,it remains uncertain whether PEG-ASNase directly induces hepatotoxicity or sensitizes hepatocytes to FFA-induced toxicity.Our results show that PEG-ASNase treatment results in hepatocyte apoptosis and lipid peroxidation.Ex vivo and in vitro studies in mouse and human WAT suggest that PEG-ASNase induces the expression of adipose triglyceride lipase(ATGL),activates the lipase,and stimulates adipose tissue lipolysis,suggesting that the FFAs from WAT may contribute to the observed liver injury.Moreover,treatment with PEG-ASNase sensitizes hepatocytes to FFA-induced lipotoxicity.Mechanistically,our RNA-sequencing(RNA-seq)analyses reveal that PEG-ASNase-induced sensitization to lipotoxicity is accompanied by the induction of Cyp2e1.We demonstrated that this sensitization effect is attenuated by both pharmacological and genetic inhibition of Cyp2e1.Our findings suggest that PEG-ASNase therapy induces WAT lipolysis and sensitizes hepatocytes to hepatic lipotoxicity in a Cyp2e1-dependent manner.

关 键 词：Liver injury ASPARAGINASE LIPOLYSIS LIPOTOXICITY Oxidative stress ATGL CYP2E1 

分 类 号：R73[医药卫生—肿瘤]