- Basic and Translational Research
- Interleukin 33 Promotes Liver Sinusoidal Endothelial Cell Dysfunction and Hepatic Fibrosis in Diabetic Mice
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Huimin Chen, Chao Gao, Li Mo, Xingzhu Yin, Li Chen, Bangfu Wu, Ying Zhao, Xueer Cheng, Chanhua Liang, Bichao Xu, Dongyan Li, Yanyan Li, Ping Yao, Yuhan Tang
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Received June 28, 2024 Accepted January 23, 2025 Published online May 22, 2025
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DOI: https://doi.org/10.4093/dmj.2024.0532
[Epub ahead of print]
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 Abstract
 PDF Supplementary Material PubReader  ePub
- Background
Interleukin 33 (IL33) drives liver fibrosis, and individuals with type 2 diabetes mellitus are more likely advanced to liver fibrosis. However, the role of IL33 in diabetic liver fibrosis remains unclear, prompting our investigation.
Methods
We developed a diabetes model in wild-type, IL33−/−, and suppression of tumorigenicity 2 (ST2−/−, IL33 receptor) mice. Furthermore, wild-type diabetic mice were injected with IL33 neutralizing antibody (αIL33). We also co-cultured human liver endothelial cells and human hepatic stellate cells to identify the role of IL33 in high palmitic acid and high glucose conditions.
Results
Hepatic collagen deposition was increased in diabetic mice, which was alleviated by IL33 knockout, ST2 knockout, or administration of αIL33. Also, αIL33 treatment blunted liver sinusoidal endothelial cell (LSEC) dysfunction and inflammation during diabetic liver fibrosis progression. Recombinant IL33 (rIL33) treatment aggravated autophagy disruption in the presence of palm acid and high glucose in LSECs, which was blunted by autophagy agonist rapamycin administration and ERK/MAPK inhibitor PD98059 treatment. Hepatic stellate cell line LX-2 co-cultured with rIL33-pretreated LSECs displayed augmented activation, which was also attenuated by rapamycin or PD98059 pretreated.
Conclusion
IL33 drives LSEC dysfunction and promotes diabetic hepatic fibrosis, thus a potential therapeutic target for diabetic liver fibrosis.
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