Serum Iron Overload Activates the SMAD Pathway and Hepcidin Expression of Hepatocytes via SMURF1
© 2024 Authors..
Background and Aims: Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.
Methods: A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.
Results: Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.
Conclusions: SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Journal of clinical and translational hepatology - 12(2024), 3 vom: 28. März, Seite 227-235 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Ning [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
BMP/SMAD pathway |
|---|
| Anmerkungen: |
Date Revised 02.03.2024 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.14218/JCTH.2023.00440 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369160878 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369160878 | ||
| 003 | DE-627 | ||
| 005 | 20240302232745.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240301s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.14218/JCTH.2023.00440 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1314.xml |
| 035 | |a (DE-627)NLM369160878 | ||
| 035 | |a (NLM)38426189 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Ning |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Serum Iron Overload Activates the SMAD Pathway and Hepcidin Expression of Hepatocytes via SMURF1 |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 02.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2024 Authors. | ||
| 520 | |a Background and Aims: Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway | ||
| 520 | |a Methods: A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin | ||
| 520 | |a Results: Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload | ||
| 520 | |a Conclusions: SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BMP/SMAD pathway | |
| 650 | 4 | |a Hemochromatosis | |
| 650 | 4 | |a Hepcidin | |
| 650 | 4 | |a Holo-transferrin | |
| 650 | 4 | |a Ubiquitin-proteasome degradation | |
| 700 | 1 | |a Yang, Pengyao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yanmeng |e verfasserin |4 aut | |
| 700 | 1 | |a Ouyang, Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Guixin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Jidong |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Anjian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of clinical and translational hepatology |d 2013 |g 12(2024), 3 vom: 28. März, Seite 227-235 |w (DE-627)NLM252610520 |x 2310-8819 |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2024 |g number:3 |g day:28 |g month:03 |g pages:227-235 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.14218/JCTH.2023.00440 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2024 |e 3 |b 28 |c 03 |h 227-235 | ||