title: Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes.
abstract: Transcriptional signaling through the antioxidant response element (ARE), orchestrated by the Nuclear factor E2-related factor 2 (Nrf2), is a major cellular defense mechanism against oxidative or electrophilic stress. Here, we reported that isoniazid (INH), a widely used antitubercular drug, displays a substantial inhibitory property against ARE activities in diverse mouse and human cells. In 3T3-L1 preadipocytes, INH concentration-dependently suppressed the ARE-luciferase reporter activity and mRNA expression of various ARE-dependent antioxidant genes under basal and oxidative stressed conditions. In keeping with our previous findings that Nrf2-ARE plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein β (C/EBPβ) and peroxisome proliferator-activated receptor γ (PPARγ), suppression of ARE signaling by INH hampered adipogenic differentiation of 3T3-L1 cells and human adipose-derived stem cells (ADSCs). Following adipogenesis induced by hormonal cocktails, INH-treated 3T3-L1 cells and ADSCs displayed significantly reduced levels of lipid accumulation and attenuated expression of C/EBPα and PPARγ. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by INH occurred in the early stage of terminal adipogenic differentiation, where reduced expression of C/EBPβ and C/EBPδ was observed. To our knowledge, the present study is the first to demonstrate that INH suppresses ARE signaling and interrupts with the transcriptional network of adipogenesis, leading to impaired adipogenic differentiation. The inhibition of ARE signaling may be a potential underlying mechanism by which INH attenuates cellular antioxidant response contributing to various complications.
authors.affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA; The First Affiliated Hospital, China Medical University, Shenyang 110001, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zheng
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Weidong
authors.initials: W
authors.lastname: Qu
authors.forename: Weiping
authors.initials: W
authors.lastname: Teng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects*; D000995:Antitubercular Agents / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*
chemical_list: D000995:Antitubercular Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C497252:CEBPD protein, human; C545013:Cebpb protein, mouse; C497253:Cebpd protein, mouse; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma; D012333:RNA, Messenger; D051743:CCAAT-Enhancer-Binding Protein-delta; D007538:Isoniazid
keywords: Adipocyte; Adipogenesis; Antioxidant response element; Isoniazid; Nrf2; Preadipocyte