Immune response gene 1 deficiency impairs Nrf2 activation and aggravates liver fibrosis in mice.

Abstract

A growing body of evidence suggests that metabolic events play essential roles in the development of liver fibrosis. Immune response gene 1 (IRG1) catalyzes the generation of itaconate, which function as a metabolic checkpoint under several pathological circumstances. In the present study, the hepatic level of IRG1 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis. And then the pathological significance of IRG1 and the pharmacological potential of 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, in liver fibrosis were investigated in mice. The results indicated that the hepatic level of IRG1 was upregulated in mice with liver fibrosis. CCl4-induced formation of fibrotic septa and deposition of collagen was aggravated in IRG1 KO mice. IRG1 deletion also resulted in increased expression of transforming growth factor beta 1 (TGF-β1), enhanced phosphorylation of Smad3, elevated level of alpha smooth muscle actin (α-SMA) and hydroxyproline, which were associated with compromised activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant system and exacerbated oxidative stress. Interestingly, supplementation with 4-OI activated Nrf2 pathway, suppressed TGF-β1 signaling and attenuated fibrogenesis. Our data indicated that upregulation of IRG1 might function as a protective response during the development of liver fibrosis, and 4-OI might have potential value for the pharmacological intervention of liver fibrosis.

• Authors: Kerui Fan, Xinyan Zan, Ying Zhi, Yongqiang Yang, Kai Hu, Xinyue Zhang, Xue Zhang, Shuang Zhao, Kun Chen, Xianqiong Gong, Rui Tian, Li Zhang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 607 Pg. 103-109 (06 04 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 35367821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Carbon Tetrachloride
• NF-E2-Related Factor 2
• Transforming Growth Factor beta1
• Irg1 protein, mouse
• Hydro-Lyases

Topics

• Animals
• Mice
• Carbon Tetrachloride (toxicity)
• Hepatic Stellate Cells (metabolism)
• Immunity
• Liver (metabolism)
• Liver Cirrhosis (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Hydro-Lyases (genetics)