Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure Through Inhibiting GSK3β-Nrf2-Mediated Hepatocyte Apoptosis and Ferroptosis

作者：Huang, Sha; Wang, Yuhua; Xie, Shunwen; Lai, Yuqi; Mo, Chan; Zeng, Ting; Kuang, Shanshan; Deng, Guanghui; Zhou, Chuying; Chen, Yuyao; Huang, Shaohui; Gao, Lei^*; Lv, Zhiping^*

来源：Cellular and Molecular Gastroenterology and Hepatology, 2022, 13(6): 1649-1672.

DOI：10.1016/j.jcmgh.2022.02.009

• ALF
• TGF beta r1
• Nrf2
• GSK3 beta
• ROS
• Apoptosis
• Ferroptosis. duces an A

Apoptosis and ferroptosis contribute to lipopolysaccharide/ D-galactosamine-induced acute liver failure, transforming growth factor /beta 1 is increased significantly during acute liver failure, and liver-specific knockout of transforming growth factor beta receptor 1 alleviates lipopolysaccharide/D-galactosamine-induced acute liver failure in mice through glycogen synthase kinase 3 beta-nuclear factor erythroid 2-related factor 2-mediated apoptosis and ferroptosis. @@@ BACKGROUND & AIMS: Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown. @@@ METHODS: Hepatic-specific transforming growth factor /5 receptor 1 knockout (TGF beta r1(&)(Δ hep-CKO)) mice and nuclear factor erythroid 2-related factor 2 knockout (Nrf2(-/-)) mice were generated and subjected to ALF. Electron microscopy was used to detect mitochondrial and other cell substructure changes during ALF. @@@ RESULTS: In this study, we noticed that lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, reactive oxygen species accumulation, and glutathione, co-enzyme Q10 system inhibition mediated ferroptosis during LPS/D-GalN-induced ALF. Rescue studies have shown that ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFOM), the inhibitor of ferroptosis, could alleviate LPS/DGalN-induced ALF. In addition, we noticed that TGF/beta 1 was increased during ALF, while ALF was relieved in TGF/beta r1(Delta hep-CKO) mice. We also noticed that liver TGF/beta r1 deficiency alleviated LPS/D-GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase 3/5 and Nrf2, a key antioxidant factor, by up-regulating the levels of glutathione peroxidase 4 (GPX4), glutamine anti porter xCT (XCT), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1), and down regulating transferrin receptor (TFR), prostaglandin-endoperoxide synthase (Ptgs2), chaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1), and cytochrome P450 reductase (POR) expression. The further supplemental experiment showed that ferroptosis was aggravated significantly in Nrf2(-/-)mice compared with its wild-type controls and reversed by ferrostatin-1. @@@ CONCLUSIONS: This study shows that TGF,beta r1 plays a critical role in mediating LPS/D-GalN-induced ALF by promoting apoptosis and ferroptosis.

• 单位
  南方医科大学