Lenvatinib prevents liver fibrosis by inhibiting hepatic stellate cell activation and sinusoidal capillarization in experimental liver fibrosis

• Published in: Journal of Cellular and Molecular Medicine Vol. 25; no. 8; pp. 4001 - 4013
• Main Authors: Ogawa, Hiroyuki, Kaji, Kosuke, Nishimura, Norihisa, Takagi, Hirotetsu, Ishida, Koji, Takaya, Hiroaki, Kawaratani, Hideto, Moriya, Kei, Namisaki, Tadashi, Akahane, Takemi, Yoshiji, Hitoshi
• Format: Journal Article
• Language: English
• Published: England Wiley 01.04.2021; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: AKT protein; Angiogenesis; Animals; Apoptosis; Bile; Capillaries; Carbon Tetrachloride; Cell activation; Cell adhesion & migration; Cell growth; Cells, Cultured; Cellulose; Chemotaxis; Collagen (type I); Extracellular signal-regulated kinase; Fibroblast growth factor 2; Fibrosis; Gene expression; Growth factors; hepatic stellate cell; Hepatic Stellate Cells; Hypertension; Injection; Kinases; Laboratory animals; lenvatinib; Liver; Liver cancer; Liver Cirrhosis; liver fibrosis; Male; Neovascularization, Pathologic; Oral administration; Original; PDGF; Phenotypes; Phenylurea Compounds; Phosphatase; Phosphorylation; Platelet-derived growth factor; Protein Kinase Inhibitors; Proteins; Quinolines; Rats; Rats, Inbred F344; Smad2 protein; Stellate cells; Transforming growth factor-b1; Vascular endothelial growth factor; Vascularization; VEGF; United States > US; Japan; liver fibrosis; hepatic stellate cell; lenvatinib; PDGF; VEGF; angiogenesis
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.16363

Molecular targeted agents are pharmacologically used to treat liver fibrosis and have gained increased attention. The present study examined the preventive effect of lenvatinib on experimental liver fibrosis and sinusoidal capillarization as well as the in vitro phenotypes of hepatic stellate cells. LX‐2, a human stellate cell line, was used for in vitro studies. In vivo liver fibrosis was induced in F344 rats using carbon tetrachloride by intraperitoneal injection for 8 weeks, and oral administration of lenvatinib was started two weeks after initial injection of carbon tetrachloride. Lenvatinib restrained proliferation and promoted apoptosis of LX‐2 with suppressed phosphorylation of extracellular signal‐regulated kinase 1/2 and AKT. It also down‐regulated COL1A1, ACTA2 and TGFB1 expressions by inhibiting the transforming growth factor‐β1/Smad2/3 pathway. Treatment with lenvatinib also suppressed platelet‐derived growth factor‐BB‐stimulated proliferation, chemotaxis and vascular endothelial growth factor‐A production, as well as basic fibroblast growth factor‐induced LX‐2 proliferation. In vivo study showed that lenvatinib attenuated liver fibrosis development with reduction in activated hepatic stellate cells and mRNA expression of profibrogenic markers. Intrahepatic neovascularization was ameliorated with reduced hepatic expressions of Vegf1, Vegf2 and Vegfa in lenvatinib‐treated rats. Collectively, these results suggest the potential use of lenvatinib as a novel therapeutic strategy for liver fibrosis.