The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP-SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP-SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo-oligomerization and ALK2-ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12-ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP-SMAD signaling and characterized by low hepcidin and high BMP6 expression.
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http://dx.doi.org/10.1002/ajh.26961 | DOI Listing |
Hepatol Commun
January 2025
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China.
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.
Elevated circulating hepcidin levels have been reported in patients with pulmonary artery hypertension (PAH). Hepcidin has been shown to promote proliferation of human pulmonary artery smooth muscle cells (PASMCs) in vitro, suggesting a potential role in PAH pathogenesis. However, the role of human pulmonary artery endothelial cells (PAECs) as either a source of hepcidin, or the effect of hepcidin on PAEC function is not as well described.
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December 2024
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. Electronic address:
Ferroptosis plays a pivotal role in the pathogenesis of ischemia-reperfusion injury (IRI). Liraglutide, as a GLP-1 receptor (GLP-1R) agonist, has exhibited extensive biological effects beyond its hypoglycemic action. Recent studies have shed light on the regulatory influence of Liraglutide on ferroptosis, yet the precise underlying mechanism remains elusive.
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Health and Environment Laboratory, Hassan II University of Casablanca, Biochemistry, Biotechnology and Immunophysiopathology Research Team, Ain Chock Faculty of Sciences, Casablanca, Morocco.
Leishmaniasis is a vector-borne parasitic infection induced by protozoa of the genus The disease spectrum ranges from skin lesions to visceral leishmaniasis, which is fatal if untreated. The cutaneous leishmaniasis is characterized by a clinical polymorphism of lesions with a broad range of severity ranging from a self-limited lesion to multiple disfiguring lesions stigmatizing the patient for life. Although iron is required for several process of infection including survival, growth and virulence, the number of studies on host iron metabolism during this infection remains limited.
View Article and Find Full Text PDFCancers (Basel)
December 2024
Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.
Colorectal cancer (CRC) is one of the most frequent neoplasms and a major cause of cancer death worldwide. Despite recent advances in treatment approaches, the prognosis of advanced CRC remains poor, thus indicating the necessity of more effective treatments for CRC patients. CRC cells produce high levels of hepcidin, a peptide hormone that binds to the membrane-bound ferroportin and promotes its internalization and degradation, thus sequestering iron into the cancer cells with the downstream effect of enhancing tumor growth.
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