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このアイテムの引用には次の識別子を使用してください: http://hdl.handle.net/10564/4452

タイトル: Cabozantinib prevents the progression of metabolic dysfunction-associated steatohepatitis by inhibiting the activation of hepatic stellate cell and macrophage and attenuating angiogenic activity
その他のタイトル: カボザンチニブは、肝星細胞とマクロファージの活性化を阻害し、血管新生活性を減弱することで代謝機能障害関連脂肪肝の進展を抑制する
著者: Matsuda, Takuya
Kaji, Kosuke
Nishimura, Norihisa
Asada, Shohei
Koizumi, Aritoshi
Tanaka, Misako
Yorioka, Nobuyuki
Tsuji, Yuki
Kitagawa, Koh
Sato, Shinya
Namisaki, Tadashi
Akahane, Takemi
Hitoshi, Yoshij
キーワード: Angiogenesis
Liver fibrosis
MASH
Inflammation
Hepatocarcinogenesis
発行日: 2024年9月
出版者: Elsevier
引用: Heliyon. 2024 Sep, vol.10, no.19, p.e38647
抄録: Cabozantinib, a multiple tyrosine kinase inhibitor targeting AXL, vascular endothelial growth factor receptor (VEGFR), and MET, is used clinically to treat certain cancers, including hepato cellular carcinoma. This study aimed to assess the impact of cabozantinib on liver fibrosis and hepatocarcinogenesis in a rat model of metabolic dysfunction-associated steatohepatitis (MASH). MASH-based liver fibrosis and hepatocarcinogenesis were induced in rats by feeding them a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for eight and 16 weeks, respectively. Cabozantinib (1 or 2 mg/kg, daily) was administered concurrently with the diet in the fibrosis model and after eight weeks in the carcinogenesis model. Treatment with cabozantinib significantly attenuated hepatic inflammation and fibrosis without affecting hepatocyte steatosis and ballooning in CDAHFD-fed rats. Cabozantinib-treated rats exhibited a marked reduction in α-smooth muscle actin+ activated hepatic stellate cell (HSC) expansion, CD68+ macrophage infiltration, and CD34+ pathological angiogenesis, along with reduced hepatic AXL, VEGF, and VEGFR2 expression. Consistently, cabozantinib downregulated the hepatic expression of profibrogenic markers (Acta2, Col1a1, Tgfb1), inflammatory cytokines (Tnfa, Il1b, Il6), and proangiogenic markers (Vegfa, Vwf, Ang2). In a cell-based assay of human activated HSCs, cabozantinib inhibited Akt activation induced by GAS6, a ligand of AXL, leading to reduced cell proliferation and profibrogenic activity. Cabozantinib also suppressed lipopolysaccharide induced proinflammatory responses in human macrophages, VEGFA-induced collagen expres sion and proliferation in activated HSCs, and VEGFA-stimulated proliferation in vascular endothelial cells. Meanwhile, administration of cabozantinib did not affect Ki67+ hepatocyte proliferation or serum albumin levels, indicating no negative impact on regenerative capacity. Treatment with cabozantinib also reduced the placental glutathione transferase+ preneoplastic lesions in CDAHFD-fed rats. In conclusion, cabozantinib shows promise as a novel option for preventing MASH progression.
内容記述: 権利情報:© 2024 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
URI: http://hdl.handle.net/10564/4452
ISSN: 2405-8440
DOI: https://doi.org/10.1016/j.heliyon.2024.e38647
学位授与番号: 24601甲第957号
学位授与年月日: 2025-03-14
学位名: 博士(医学)
学位授与機関: 奈良県立医科大学
出現コレクション:2024年度

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