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AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway.
Zhang, Qing-Qi; Chen, Qian; Cao, Pan; Shi, Chun-Xia; Zhang, Lu-Yi; Wang, Lu-Wen; Gong, Zuo-Jiong.
Afiliación
  • Zhang QQ; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • Chen Q; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • Cao P; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • Shi CX; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • Zhang LY; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • Wang LW; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • Gong ZJ; Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: zjgong@163.com.
Hepatobiliary Pancreat Dis Int ; 23(1): 43-51, 2024 Feb.
Article en En | MEDLINE | ID: mdl-36966125
BACKGROUND: Acute liver failure (ALF) is an unpredictable and life-threatening critical illness. The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure. METHODS: Animals were divided into 3 groups, normal, thioacetamide (TAA, ALF model) and TAA + AGK2. Cultured L02 cells were divided into 5 groups, normal, TAA, TAA + mitofusin 2 (MFN2)-siRNA, TAA + AGK2, and TAA + AGK2 + MFN2-siRNA groups. The liver histology was evaluated with hematoxylin and eosin staining, inositol-requiring enzyme 1 (IRE1), activating transcription factor 6ß (ATF6ß), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylated-PERK (p-PERK). C/EBP homologous protein (CHOP), reactive oxygen species (ROS), MFN2 and glutathione peroxidase 4 (GPX4) were measured with Western blotting, and cell viability and liver chemistry were also measured. Mitochondria-associated endoplasmic reticulum membranes (MAMs) were measured by immunofluorescence. RESULTS: The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis, which were reduced by AGK2 pre-treatment. In comparison to the normal group, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ in the TAA-induced ALF model group were significantly increased, which were decreased by AGK2 pre-treatment. The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group, which were enhanced by AGK2 pre-treatment. Compared with the TAA-induced L02 cell, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group. AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell. Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells. CONCLUSIONS: The data suggested that AGK2 pre-treatment had hepatoprotective role in TAA-induced ALF via upregulating the expression of MFN2 and then inhibiting PERK and ferroptosis pathway in ALF.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fallo Hepático Agudo / Ferroptosis Tipo de estudio: Prognostic_studies Idioma: En Revista: Hepatobiliary Pancreat Dis Int Asunto de la revista: GASTROENTEROLOGIA Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fallo Hepático Agudo / Ferroptosis Tipo de estudio: Prognostic_studies Idioma: En Revista: Hepatobiliary Pancreat Dis Int Asunto de la revista: GASTROENTEROLOGIA Año: 2024 Tipo del documento: Article