Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects. FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology. FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression. Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNFα and IL6 expression. In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter. These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations. These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNFα/ NF-κB mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor.

FGF23 and Fetuin-A interaction in the liver and in the circulation / D. Mattinzoli, M. Ikehata, K. Tsugawa, C.M. Alfieri, P. Dongiovanni, E. Trombetta, L. Valenti, A. Puliti, L. Lazzari, P. Messa. - In: INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES. - ISSN 1449-2288. - 14:6(2018 Apr 25), pp. 586-598. [10.7150/ijbs.23256]

FGF23 and Fetuin-A interaction in the liver and in the circulation

Alfieri, Carlo M.;Dongiovanni, Paola;Valenti, Luca;Messa, Piergiorgio
2018-04-25

Abstract

Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects. FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology. FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression. Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNFα and IL6 expression. In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter. These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations. These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNFα/ NF-κB mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor.
Chronic kidney disease; Circulation; Fetuin-A; FGF23; Inflammation; Liver; Ecology, Evolution, Behavior and Systematics; Applied Microbiology and Biotechnology; Molecular Biology; Developmental Biology; Cell Biology
Settore MED/14 - Nefrologia
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Article (author)
File in questo prodotto:
File Dimensione Formato  
Mattinzoli D, Messa P FGF23 and Fetuin in Liver cells Int J Biol Sci 2018.pdf

accesso aperto

2.15 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/587874
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 7
social impact