Int J Biol Sci 2024; 20(2):606-620. doi:10.7150/ijbs.90781 This issue Cite

Research Paper

TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production

Eunhye Jung1,*, Eun Bok Baek1,*, Eun-Ju Hong1, Jee Hyun Kang1, Suyoung Park1, Sehee Park2, Eui-Ju Hong1, Young-Eun Cho3, Je-Won Ko1, Young-Suk Won2,✉, Hyo-Jung Kwon1,✉

1. College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.
2. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 28116, Republic of Korea.
3. Andong National University, Andong 36729, Republic of Korea.
* These authors contributed equally to this work.

Citation:
Jung E, Baek EB, Hong EJ, Kang JH, Park S, Park S, Hong EJ, Cho YE, Ko JW, Won YS, Kwon HJ. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int J Biol Sci 2024; 20(2):606-620. doi:10.7150/ijbs.90781. https://www.ijbs.com/v20p0606.htm
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Abstract

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Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor β-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.

Keywords: alcohol-associated liver disease, eNOS, liver sinusoidal endothelial cells, NO, TAK1, TXNIP


Citation styles

APA
Jung, E., Baek, E.B., Hong, E.J., Kang, J.H., Park, S., Park, S., Hong, E.J., Cho, Y.E., Ko, J.W., Won, Y.S., Kwon, H.J. (2024). TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. International Journal of Biological Sciences, 20(2), 606-620. https://doi.org/10.7150/ijbs.90781.

ACS
Jung, E.; Baek, E.B.; Hong, E.J.; Kang, J.H.; Park, S.; Park, S.; Hong, E.J.; Cho, Y.E.; Ko, J.W.; Won, Y.S.; Kwon, H.J. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int. J. Biol. Sci. 2024, 20 (2), 606-620. DOI: 10.7150/ijbs.90781.

NLM
Jung E, Baek EB, Hong EJ, Kang JH, Park S, Park S, Hong EJ, Cho YE, Ko JW, Won YS, Kwon HJ. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int J Biol Sci 2024; 20(2):606-620. doi:10.7150/ijbs.90781. https://www.ijbs.com/v20p0606.htm

CSE
Jung E, Baek EB, Hong EJ, Kang JH, Park S, Park S, Hong EJ, Cho YE, Ko JW, Won YS, Kwon HJ. 2024. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int J Biol Sci. 20(2):606-620.

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