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- W4387168049 abstract "ABSTRACT Objective Bmp6 knockout (KO) mice progressively accumulate a significant amount of iron in their liver as they age due to a defect in hepcidin (Hamp) expression and an upregulation of the iron exporter ferroportin (Fpn). In this study, we conducted a comprehensive investigation of the hepatic iron overload phenotype, with specific emphasis on the cellular and subcellular localization of Fpn in Bmp6 KO mice. Materials and Methods Livers obtained from Bmp6 knockout (KO) mice at different developmental stages were utilized for the quantification of iron content, investigation of iron distribution, histological analysis, histoimmunofluorescence assays performed on paraffin-embedded sections, confocal microscopy examinations, subcellular membrane fractionation, and western blot analysis. Results In Bmp6 KO livers, iron overload increased with age and was not homogeneous, with certain hepatic lobes and specific areas in liver sections showing more pronounced iron accumulation. In young mice, iron accumulated mostly in the centrilobular zone where low Fpn expression was observed. Fpn was strongly detected in periportal Kupffer cells and at the apical membrane of periportal hepatocytes lining the sinusoidal capillaries. The zonal distribution of iron tended to disappear with age in strongly iron-overloaded areas, with the appearance of large cellular aggregates strongly positive for Fpn, iron, and ceroid/lipofuscin. At the subcellular level, hepatic Fpn seemed to concentrate in specific cell surface compartments and was enriched in a lipid raft fraction. Conclusions Unregulated expression of Fpn on the cell surface of periportal macrophages and hepatocytes results in centrilobular iron overload within hepatocytes. In areas of pronounced iron overload, Fpn expression is present in lipogranulomas, identified as aggregations of macrophages accumulating hemosiderin and ceroid/lipofuscin pigments. These lesions likely form due to the phagocytosis of sideronecrotic/ferroptotic hepatocytes by macrophages. In contrast to the duodenal form of Fpn, both splenic and hepatic Fpn demonstrated robust enrichment within lipid rafts. The observed variations in the subcellular localization of Fpn could play a significant role in influencing the transporter’s iron transport activity and/or its regulation by hepcidin." @default.
- W4387168049 created "2023-09-30" @default.
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- W4387168049 date "2023-09-29" @default.
- W4387168049 modified "2023-10-16" @default.
- W4387168049 title "NEW INSIGHTS INTO THE HEPATIC IRON PHENOTYPE OF BMP6 KNOCKOUT MICE" @default.
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- W4387168049 doi "https://doi.org/10.1101/2023.09.28.559941" @default.
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