NAG-1/GDF15 modulates hepcidin expression through STAT3 and SMAD pathways

Area of Science:

• Molecular Biology
• Endocrinology
• Iron Metabolism

Background:

• Hepcidin is a liver hormone regulating iron homeostasis and implicated in anemia of inflammation (AI).
• Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 (NAG-1), also known as GDF15, is investigated for its role in hepcidin regulation.

Purpose of the Study:

• To investigate the regulatory role of NAG-1 in modulating hepcidin expression.
• To elucidate the molecular mechanisms by which NAG-1 affects hepcidin transcription.

Main Methods:

• Utilized NAG-1 transgenic mice to assess in vivo effects on hepcidin expression.
• Established HepG2 cell lines overexpressing wild-type (WT) or mutant NAG-1 (R193A).
• Analyzed the impact of NAG-1 on IL-6- and BMP6-induced hepcidin expression and signaling pathways (JAK/STAT3, BMP6/SMAD).

Main Results:

• Elevated circulating NAG-1 in transgenic mice correlated with reduced hepatic hepcidin expression.
• Both WT and R193A NAG-1 suppressed IL-6- and BMP6-induced hepcidin expression in HepG2 cells.
• NAG-1 inhibited hepcidin transcription by reducing STAT3 activation and Smad1/5/9 phosphorylation, key components of JAK/STAT3 and BMP6/SMAD pathways.

Conclusions:

• NAG-1 acts as a negative regulator of hepcidin transcription.
• The pro-form of NAG-1 possesses significant biological activity in suppressing hepcidin.
• Findings offer therapeutic insights for managing anemia of inflammation by targeting iron metabolism via NAG-1 modulation.