title: Apoptotic response through a high mobility box 1 protein-dependent mechanism in LPS/GalN-induced mouse liver failure and glycyrrhizin-mediated inhibition.
abstract: HMGB1 is a nuclear component involved in nucleosome stabilization and transcription regulation, but extracellularly it is able to serve as a potential late mediator of lethality. In the present study, we explored inflammation-promoting activity of HMGB1 and blockade of extracellular release of HMGB1 by glycyrrhizin (GL) in LPS/GalN-triggered mouse liver injury. At 1 to 10 h after LPS/GalN-treatment, mice were anesthetized to collect blood from heart puncture, and serum transaminase and HMGB1 were evaluated. Administration of LPS/GalN precipitated tissue injury associated with time-dependent alteration in HMGB1 serum levels. At 8 h nuclear immunoreactive products were remarkably reduced and extracellular HMGB1 expression was found exclusively in the pericentral foci. The treatment with GL significantly down-regulated the serum levels of ALT, AST, and HMGB1 in addition to the strong inhibition of tissue injury and extracellular immunoreactivity to HMGB1 and to acetylated-lysine. Furthermore, GL brought about a significant decrease in the number of apoptotic hepatocytes labeled with TUNEL-method. On the basis of these results, three apoptosis-associated genes were identified with microarray analysis and real-time PCR. The ChIP-assay revealed the binding of HMGB1 protein to Gsto1 promoter sequence in LPS/GalN-treated mice and the remarkable decrease in combined HMGB1 protein by GL. The current findings claim that a single injection of LPS/GalN might stimulate apoptosis of hepatocytes through the binding of HMGB1 protein to Gsto1 promoter region and that GL-treatment might prevent the apoptosis and inflammatory infiltrates caused with LPS/GalN-injection by disturbing the binding of HMGB1 protein to Gsto1 promoter sequence.
authors.affiliation: Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kuroda
authors.affiliation: Research Center of Electron Microscopy, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Geriatric Dentistry, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors.forename: Yaiko
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan; Liver Research Unit, Minophagen Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Wake
authors.affiliation: Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sato
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005688:Galactosamine; D005786:Gene Expression Regulation / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D017093:Liver Failure / Q000097:blood / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C000593873:Ager protein, mouse; D002352:Carrier Proteins; C117709:Gsto1 protein, mouse; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D051197:Toll-Like Receptor 4; D019695:Glycyrrhizic Acid; D005688:Galactosamine; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D006655:Histone Deacetylases