title: Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)-binding Protein (CBP)/β-Catenin Reduces Liver Fibrosis in Mice.
abstract: Wnt/β-catenin is involved in every aspect of embryonic development and in the pathogenesis of many human diseases, and is also implicated in organ fibrosis. However, the role of β-catenin-mediated signaling on liver fibrosis remains unclear. To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP)/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 or BDL. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs) and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80(+) CD11b(+) and Ly6C(low) CD11b(+) macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP)-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. In conclusion, targeting the CBP/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis.
authors: Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors: Yosuke
authors: Y
authors: Osawa
authors: Department of Molecular Medical Research and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Keisuke
authors: K
authors: Oboki
authors: Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors: Jun
authors: J
authors: Imamura
authors: Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors: Ekumi
authors: E
authors: Kojika
authors: Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors: Yukiko
authors: Y
authors: Hayashi
authors: Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors: Tsunekazu
authors: T
authors: Hishima
authors: Department of Gastroenterology and Hepatology, Kochi University School of Medicine Kohasu, Okouchou, Nankoku, Kochi 789-8505, Japan.
authors: Toshiji
authors: T
authors: Saibara
authors: Department of Molecular Medical Research and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Futoshi
authors: F
authors: Shibasaki
authors: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Michinori
authors: M
authors: Kohara
authors: Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors: Kiminori
authors: K
authors: Kimura
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D050882:CREB-Binding Protein
keywords: BDL, bile duct ligation; Beta-catenin; CBP, CREB-binding protein; CCL, c–c motif ligand; CCl4, carbon tetrachloride; CREB, cAMP-response element-binding protein; CXCL, c–x–c motif ligand; Fibrosis; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCV, hepatitis C virus; HSC, hepatic stellate cell; Hepatic stellate cell; H–E, hematoxylin and eosin; Liver; MMP, matrix metalloproteinase; Macrophage; PBDL, partial BDL; SPARC, secreted protein acidic and rich in cysteine; TGF-β, transforming growth factor; TIMP-1, tissue inhibitor of metalloproteinase; αSMA, α-smooth muscle actin,