title: Involvement of the nuclear high mobility group B1 peptides released from injured hepatocytes in murine hepatic fibrogenesis.
abstract: This study investigated the pro-fibrogenic role of high mobility group box 1 (HMGB1) peptides in liver fibrogenesis. An animal model of carbon tetrachloride (CCl4)-induced liver fibrosis was used to examine the serum HMGB1 levels and its intrahepatic distribution. The increased serum HMGB1 levels were positively correlated with elevation of transforming growth factor-β1 (TGF-β1) and collagen deposition during fibrogenesis. The cytoplasmic distribution of HMGB1 was noted in the parenchymal hepatocytes of fibrotic livers. In vitro studies confirmed that exposure to hydrogen peroxide and CCl4 induced an intracellular mobilization and extracellular release of nuclear HMGB1 peptides in clone-9 and primary hepatocytes, respectively. An uptake of exogenous HMGB1 by hepatic stellate cells (HSCs) T6 cells indicated a possible paracrine action of hepatocytes on HSCs. Moreover, HMGB1 dose-dependently stimulated HSC proliferation, up-regulated de novo synthesis of collagen type I and α-smooth muscle actin (α-SMA), and triggered Smad2 phosphorylation and its nuclear translocation through a TGF-β1-independent mechanism. Blockade with neutralizing antibodies and gene silencing demonstrated the involvement of the receptor for advanced glycation end-products (RAGE), but not toll-like receptor 4, in cellular uptake of HMGB1 and the HMGB1-mediated Smad2 and ERK1/2 phosphorylation as well as α-SMA up-regulation in HSC-T6 cells. Furthermore, anti-RAGE treatment significantly ameliorated CCl4-induced liver fibrosis. In conclusion, the nuclear HMGB1 peptides released from parenchymal hepatocytes during liver injuries may directly activate HSCs through stimulating HSC proliferation and transformation, eventually leading to the fibrotic changes of livers. Blockade of HMGB1/RAGE signaling cascade may constitute a therapeutic strategy for treatment of liver fibrosis.
authors: Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
authors: Ying-Hsien
authors: YH
authors: Kao
authors: Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan.
authors: Yu-Chun
authors: YC
authors: Lin
authors: Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan.
authors: Ming-Shian
authors: MS
authors: Tsai
authors: Department of Medical Education, E-DA Hospital, Kaohsiung, Taiwan.
authors: Cheuk-Kwan
authors: CK
authors: Sun
authors: Translational Research Center and Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Shyng-Shiou
authors: SS
authors: Yuan
authors: Department of Obstetrics and Gynecology, E-DA Hospital, Kaohsiung, Taiwan.
authors: Chih-Yang
authors: CY
authors: Chang
authors: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: jawanb@adm.cghm.org.tw.
authors: Bruno
authors: B
authors: Jawan
authors: Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: pohuang1115@ntu.edu.tw.
authors: Po-Huang
authors: PH
authors: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016877:Oxidants / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D016877:Oxidants; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006861:Hydrogen Peroxide; D002251:Carbon Tetrachloride
keywords: Hepatic stellate cells; Oxidative stress; RAGE; Smad2 phosphorylation; TGF-β1 signaling; TLR4