title: Borrelidin Isolated from Streptomyces sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells via Several Factors Including GATA-Binding Protein 3.
abstract: An inhibitor of 3T3-L1 adipocyte differentiation was isolated from Streptomyces sp. TK08330 and identified by spectroscopy as the 18-membered macrolide borrelidin. Treatment with 1.0 μM borrelidin suppressed intracellular lipid accumulation by 80% and inhibited the expression of adipocyte-specific genes. Borrelidin suppressed the mRNA expression of two master regulators of adipocyte differentiation, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein (C/EBPα). Studies on well-known upstream regulators of PPARγ revealed that borrelidin down-regulated C/EBPδ mRNA expression but did not affect expression of C/EBPβ. Borrelidin increased mRNA expression of negative regulators of differentiation such as GATA-binding protein (GATA) 3, Krüppel-like factor (KLF) 3 and KLF7, as well as positive regulators, KLF4, KLF6 and KLF15, at early stages of differentiation. To elucidate a primary mediator of borrelidin differentiation inhibitory activity, small interfering RNA (siRNA) transfection experiments were performed. The mRNA expression of PPARγ, which was down-regulated by borrelidin, was not changed by KLF3 and KLF7 siRNA treatment. In contrast, expression of PPARγ in GATA-3 siRNA-treated cells was not significantly different from that of control siRNA-treated cells. Borrelidin significantly inhibited lipid accumulation in control siRNA-treated cells, and treatment with GATA-3 siRNA slightly reduced the inhibitory effect of borrelidin. These results indicate that borrelidin inhibited adipocyte differentiation partially via GATA-3.
authors.affiliation: Graduate School of Science and Engineering, Ritsumeikan University.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kondo
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Tokuyama
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Imamura
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology; D050990:GATA3 Transcription Factor / Q000235:genetics*; D051275:Glucose Transporter Type 4 / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013302:Streptomyces / Q000737:chemistry
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005233:Fatty Alcohols; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051275:Glucose Transporter Type 4; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; C005066:borrelidin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1