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

Sho Wakamatsu; Teruo Jojima; Masaaki Hashiguchi; Haruka Kishi; Takafumi Niitani; Shintaro Sakurai; Toshie Iijima; Takahiko Kogai; Takuya Tomaru; Isao Usui; Yoshimasa Aso

doi:10.1016/j.jdiacomp.2023.108650

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

J Diabetes Complications. 2024 Jan;38(1):108650. doi: 10.1016/j.jdiacomp.2023.108650. Epub 2023 Nov 23.

Authors

Affiliations

¹ Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan.
² Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan. Electronic address: [email protected].
³ Department of Cell Biology, Institute of Advanced Medical Sciences, Nippon Medical School, 1-1-5, Tokyo 113-8602, Japan.
⁴ Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi 321-0293, Japan.
⁵ Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi 321-0293, Japan. Electronic address: [email protected].

PMID: 38035640
DOI: 10.1016/j.jdiacomp.2023.108650

Abstract

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.

Keywords: Interleukin-33; Liver fibrosis; MCP-1; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Sodium-glucose co-transporter 2 inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / prevention & control
Diabetes Mellitus* / drug therapy
Disease Models, Animal
Interleukin-33 / metabolism
Interleukin-33 / therapeutic use
Liver / metabolism
Liver Cirrhosis / drug therapy
Liver Cirrhosis / etiology
Liver Cirrhosis / prevention & control
Liver Neoplasms* / prevention & control
Mice
Non-alcoholic Fatty Liver Disease* / complications
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / metabolism
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
Sorbitol* / analogs & derivatives

Substances

1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol
Interleukin-33
Sodium-Glucose Transporter 2 Inhibitors
Sorbitol
Ccl2 protein, mouse
Il33 protein, mouse