Abstract | AIMS: RESULTS: We showed that AMPK mediated the inhibition of STAT3, hepcidin, and AI by H2S during inflammation. Moreover, pharmacological and genetic activation of AMPK ameliorated hepcidin production, corrected iron dysregulation, and relieved hypoferremia and anemia in both acute and chronic inflammation models in mice. Mechanistic studies indicated that AMPK suppressed STAT3/ hepcidin activation by promoting proteasome-mediated Janus kinase 2 (JAK2) degradation, which was dependent on the intact function of suppressor of cytokine signaling 1 (SOCS1) and increased interactions between SOCS1 and JAK2. Most importantly, the AMPK activator metformin was associated with decreased serum hepcidin content and anemia morbidity in Chinese type 2 diabetes mellitus patients. INNOVATION: This is the first study to demonstrate the inhibition of inflammatory hepcidin and AI by AMPK-induced JAK2 degradation. Our work uncovered AMPK as a novel therapeutic target, and metformin as a potential therapy against AI. CONCLUSION: The present work demonstrated that AMPK mediated the therapeutic effects of H2S and relieved AI by promoting SOCS1-mediated JAK2 degradation. Antioxid. Redox Signal. 27, 251-268.
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Authors | Minjun Wang, Hong Xin, Wenbo Tang, Yiming Li, Zhaoyun Zhang, Linling Fan, Lei Miao, Bo Tan, Xiling Wang, Yi Zhun Zhu |
Journal | Antioxidants & redox signaling
(Antioxid Redox Signal)
Vol. 27
Issue 5
Pg. 251-268
(08 10 2017)
ISSN: 1557-7716 [Electronic] United States |
PMID | 27923278
(Publication Type: Journal Article)
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Chemical References |
- Hepcidins
- STAT3 Transcription Factor
- Suppressor of Cytokine Signaling 1 Protein
- Janus Kinase 2
- Turpentine
- Hydrogen Sulfide
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Topics |
- Anemia
(blood, drug therapy, metabolism)
- Animals
- Cell Line
- Cells, Cultured
- Fluorescent Antibody Technique
- Hepcidins
(metabolism)
- Humans
- Hydrogen Sulfide
(therapeutic use)
- Immunoblotting
- Immunoprecipitation
- Inflammation
(blood, drug therapy, metabolism)
- Janus Kinase 2
(metabolism)
- Mice
- Mice, Inbred C57BL
- Real-Time Polymerase Chain Reaction
- STAT3 Transcription Factor
(metabolism)
- Signal Transduction
(drug effects)
- Suppressor of Cytokine Signaling 1 Protein
(metabolism)
- Turpentine
(toxicity)
- Ubiquitination
(drug effects)
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