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論文
- タイトル
- タイトル（英）
- Molecular insights of a CBP/β-catenin-signaling inhibitor on nonalcoholic steatohepatitis-induced liver fibrosis and disorder.
- 参照URL
- https://researchmap.jp/dyamane/published_papers/43943579
- 著者
- 著者（英）
- Kenzaburo Yamaji,Sadahiro Iwabuchi,Yuko Tokunaga,Shinichi Hashimoto,Daisuke Yamane,Sakiko Toyama,Risa Kono,Bouchra Kitab,Kyoko Tsukiyama-Kohara,Yosuke Osawa,Yukiko Hayashi,Tsunekazu Hishima,Chise Tateno,Kiminori Kimura,Takeshi Okanoue,Michinori Kohara
- 担当区分
- 概要
- 概要（英）
- Nonalcoholic steatohepatitis (NASH) is a progressive fibrotic disease associated with an increased risk of developing hepatocellular carcinoma; at present, no efficient therapeutic strategy has been established. Herein, we examined the efficacy of PRI-724, a potent inhibitor of CBP/β-catenin signaling, for treating NASH-related liver fibrosis and disorder and characterized its mechanism. Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice exhibited NASH-induced liver fibrosis that is characterized by steatosis, lobular inflammation, hepatocellular injury and collagen fibrils. To examine the therapeutic effect, CDAHFD-fed mice were administered PRI-724. Serum levels of ALT and pro-fibrotic molecule, i.e. Mac-2 bp, alpha smooth muscle actin, type I and type III collagens, decreased significantly. mRNA levels of the matrix metalloproteinases Mmp8 and Mmp9 in the liver were significantly increased, and increases in the abundance of MMP9-producing neutrophils and macrophages were observed. Marco+Mmp9+Cd68+ Kupffer cells were only observed in the livers of mice treated with PRI-724, and Mmp9 expression in Marco+Cd68+ Kupffer cells increased 4.3-fold. Moreover, hepatic expression of the lipid metabolism regulator, pyruvate dehydrogenase kinase 4 and liver lipid droplets also decreased significantly. PRI-724-treated NASH mice not only recovered from NASH-related liver fibrosis through the effect of PRI-724 down-regulating the expression of pro-fibrotic genes and up-regulating the expression of anti-fibrotic genes, but they also recovered from NASH-induced liver disorder. PRI-724, a selective CBP/β-catenin inhibitor, thus shows a potent therapeutic effect for NASH-related liver fibrosis and for decreasing adipose tissue in the liver.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
- 巻
- 166
- 号
- 開始ページ
- 115379
- 終了ページ
- 115379
- 出版年月
- 2023年10月
- 査読の有無
- 査読有り
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1016/j.biopha.2023.115379
- 共同研究・競争的資金等の研究課題
研究者
山根 大典
(ヤマネ ダイスケ)