Hepcidin inhibits hepatocyte apoptosis through the PERK pathway in acute liver injury and fibrosis.

Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 101695860 Publication Model: eCollection Cited Medium: Internet ISSN: 2471-254X (Electronic) Linking ISSN: 2471254X NLM ISO Abbreviation: Hepatol Commun Subsets: MEDLINE

Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc.
Original Publication: [Hoboken, NJ] : Wiley Periodicals, Inc. on behalf of the American Association for the Study of Liver Diseases, [2017]-

Hepcidins*/metabolism ; Hepcidins*/genetics ; Hepatocytes*/metabolism ; Hepatocytes*/pathology ; Apoptosis* ; eIF-2 Kinase*/metabolism ; Mice, Knockout* ; Liver Cirrhosis*/pathology ; Liver Cirrhosis*/genetics ; Liver Cirrhosis*/metabolism ; Carbon Tetrachloride* ; Mice, Inbred C57BL*; Animals ; Mice ; Signal Transduction ; Male ; Disease Models, Animal ; Chemical and Drug Induced Liver Injury/pathology ; Chemical and Drug Induced Liver Injury/genetics

Background: Hepcidin, a peptide hormone primarily produced by the liver, regulates iron metabolism by interacting with its receptor, ferroportin. Studies have demonstrated that hepcidin participates in the progression of liver fibrosis by regulating HSC activation, but its regulatory effect on hepatocytes remains largely unknown.
Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 wild-type (WT) and hepcidin knockout (Hamp-/-) mice. Liver injury and inflammation were assessed in WT and Hamp-/- mice at 24 and 48 hours following acute CCl4 exposure. In addition, transcriptomic sequencing of primary hepatocytes was performed to compare gene expression profiles between WT and Hamp-/- mice 24 hours after liver injury. The function of the identified molecule Eif2ak3/PERK (protein kinase R(PKR)-like endoplasmic reticulum kinase), was evaluated both in vitro and in vivo.
Results: We found that serum hepcidin significantly increased during the progression of liver fibrosis induced by CCl4 and bile duct ligation. In addition, CCl4-treated Hamp-/- mice developed more severe liver injury, liver fibrosis, and hepatocyte apoptosis, with elevated Bax and decreased Bcl-2 expression, compared to the WT mice. Transcriptomic analysis of primary hepatocytes revealed that PERK was upregulated in Hamp-/- mice after CCl4 treatment, promoting apoptosis by regulating Bax and Bcl-2 expression. Subsequently, we demonstrated that hepcidin prevents hepatocyte apoptosis by inhibiting PERK both in vitro and in vivo.
Conclusions: Hepcidin inhibits hepatocyte apoptosis through suppression of the PERK pathway, highlighting its protective role in liver fibrosis and identifying a potential therapeutic target for the treatment of liver fibrosis.
(Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

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0 (Hepcidins)
EC 2.7.11.1 (eIF-2 Kinase)
CL2T97X0V0 (Carbon Tetrachloride)
EC 2.7.11.1 (PERK kinase)
0 (Hamp protein, mouse)

Date Created: 20241219 Date Completed: 20241219 Latest Revision: 20241219

20241219

10.1097/HC9.0000000000000604

39699302