Bmp6 Expression in Murine Liver Non Parenchymal Cells: A Mechanism to Control their High Iron Exporter Activity and Protect Hepatocytes from Iron Overload?

Abstract

Bmp6 is the main activator of hepcidin, the liver hormone that negatively regulates plasma iron influx by degrading the sole iron exporter ferroportin in enterocytes and macrophages. Bmp6 expression is modulated by iron but the molecular mechanisms are unknown. Although hepcidin is expressed almost exclusively by hepatocytes (HCs), Bmp6 is produced also by non-parenchymal cells (NPCs), mainly sinusoidal endothelial cells (LSECs). To investigate the regulation of Bmp6 in HCs and NPCs, liver cells were isolated from adult wild type mice whose diet was modified in iron content in acute or chronic manner and in disease models of iron deficiency (Tmprss6 KO mouse) and overload (Hjv KO mouse). With manipulation of dietary iron in wild-type mice, Bmp6 and Tfr1 expression in both HCs and NPCs was inversely related, as expected. When hepcidin expression is abnormal in murine models of iron overload (Hjv KO mice) and deficiency (Tmprss6 KO mice), Bmp6 expression in NPCs was not related to Tfr1. Despite the low Bmp6 in NPCs from Tmprss6 KO mice, Tfr1 mRNA was also low. Conversely, despite body iron overload and high expression of Bmp6 in NPCs from Hjv KO mice, Tfr1 mRNA and protein were increased. However, in the same cells ferritin L was only slightly increased, but the iron content was not, suggesting that Bmp6 in these cells reflects the high intracellular iron import and export. We propose that NPCs, sensing the iron flux, not only increase hepcidin through Bmp6 with a paracrine mechanism to control systemic iron homeostasis but, controlling hepcidin, they regulate their own ferroportin, inducing iron retention or release and further modulating Bmp6 production in an autocrine manner. This mechanism, that contributes to protect HC from iron loading or deficiency, is lost in disease models of hepcidin production.

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

“…Iron parameters such as transferrin saturation, serum iron, liver iron content (LIC), and spleen iron content (SIC) were analyzed as previously described 24,25 and according to the method recommended by Torrance. 26 Briefly, 100 mg of tissue were homogenized with 150 mL water in a FastPrep-24 Instrument (MP Biomedicals, Santa Ana, CA) for 60 seconds at 6 m/s, mixed with a solution of HCl 30%/trichloracetic acid 10% in a final volume of 1.5 mL, and kept overnight at 65°C before performing the colorimetric assay.…”

Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice

“…Liver cell isolation experiments suggest that nonparenchymal cells (NPCs), including sinusoidal endothelial cells (SECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs) rather than hepatocytes, are the predominant source of BMP6 in the liver. [22][23][24] However, Bmp6 mRNA and protein were reported to be induced by The online version of this article contains a data supplement.…”

“…on June 7, 2019. by guest www.bloodjournal.org From iron in hepatocytes. 19,24,25 Importantly, functional data are lacking that demonstrate which liver cell population is the main source of BMP6 that is crucial for maintaining systemic iron balance. To answer this fundamental question, we generated mice with a conditional knockout of Bmp6 in different liver cell populations.…”

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

“…In iron-replete mice, hepatic expression of BMP6 increases [43]. In the liver, BMP6 is mainly expressed in the sinusoidal endothelial cells [42,44] and induces hepcidin expression upon iron loading in a paracrine manner (Fig. 2).…”