Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor

• Published in: Journal of diabetes and its complications 2024-01, Vol.38 (1), p.108650-108650, Article 108650
• Main Authors: Wakamatsu, Sho, Jojima, Teruo, Hashiguchi, Masaaki, Kishi, Haruka, Niitani, Takafumi, Sakurai, Shintaro, Iijima, Toshie, Kogai, Takahiko, Tomaru, Takuya, Usui, Isao, Aso, Yoshimasa
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Antibodies; Carcinoma, Hepatocellular - prevention & control; Cell cycle; Cell growth; Collagen; Cytokines; Diabetes; Diabetes Mellitus - drug therapy; Disease Models, Animal; Glucose; Interleukin-33 - metabolism; Interleukin-33 - therapeutic use; Liver - metabolism; Liver cancer; Liver Cirrhosis - drug therapy; Liver Cirrhosis - etiology; Liver Cirrhosis - prevention & control; Liver diseases; Liver Neoplasms - prevention & control; Mice; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Proteins; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Sorbitol - analogs & derivatives
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/j.jdiacomp.2023.108650

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.