Liver sinusoidal endothelial cells induce BMP6 expression in response to non-transferrin-bound iron

Area of Science:

• Hepatology and Iron Metabolism
• Cellular Signaling and Transcriptomics
• Molecular Mechanisms of Homeostasis

Background:

• Systemic iron overload triggers adaptive responses, including bone morphogenetic protein 6 (BMP6) induction in liver sinusoidal endothelial cells (LSECs).
• BMP6 signaling activates hepcidin (HAMP), the iron hormone, in hepatocytes to regulate systemic iron levels.
• The precise mechanism by which LSECs sense and respond to iron overload remains incompletely understood.

Purpose of the Study:

• To investigate the role of transferrin receptor 1 (Tfr1) in endothelial cell iron sensing.
• To elucidate the molecular mechanisms underlying LSEC responses to systemic iron overload.
• To identify key signaling pathways and cell types involved in iron homeostasis.

Main Methods:

• Generation of TfrcTek-Cre mice for endothelial cell-specific ablation of Tfr1.
• Single-cell transcriptomic analysis of LSECs and other liver cells in response to iron challenges.
• Quantification of liver iron content (LIC) and Bmp6/Hamp mRNA levels.
• Induction of iron overload using high-dietary iron and holo-transferrin injection.

Main Results:

• Endothelial cell-specific Tfr1 ablation resulted in modest increases in LIC but did not abolish Bmp6 and Hamp induction.
• High dietary iron induced non-transferrin bound iron (NTBI), correlating with Bmp6 and Hamp mRNA levels and altering LSEC transcriptomes.
• NTBI accumulation promoted oxidative stress, leading to robust induction of Bmp6 via nuclear factor erythroid 2-related factor 2 (Nrf2) and Myc target genes in LSECs.

Conclusions:

• LSECs internalize NTBI during iron overload, inducing oxidative stress and transcriptional upregulation of Bmp6 through the Nrf2 pathway.
• Tfr1 plays a role in LSEC iron sensing, particularly under conditions of low systemic iron.
• LSECs and midzonal hepatocytes are key cell types responding to iron challenges, highlighting their importance in maintaining iron homeostasis.