Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate-globotriaosylceramide (Gb3Cer)-B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease-FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Herein, we provide a comprehensive overview of the biochemical and structural abnormalities in pancreatic tissue from two male FD patients with blood group B. In both patients, we found major accumulation of a variety of complex B-GSLs carrying predominantly hexa- and hepta-saccharide structures. The subcellular pathology was dominated by deposits containing B-glycoconjugates and autofluorescent ceroid. The contribution of Gb3Cer to the storage was minor. This abnormal storage pattern was specific for the pancreatic acinar epithelial cells. Other pancreatic cell types including those of islets of Langerhans were affected much less or not at all.Altogether, we provide evidence for a key role of B-antigens in the biochemical and morphological pathology of the exocrine pancreas in FD patients with blood group B. We believe that our findings will trigger further studies aimed at assessing the potential pancreatic dysfunction in this disease.
- MeSH
- ABO systém krevních skupin metabolismus MeSH
- acinární buňky metabolismus ultrastruktura MeSH
- beta-buňky metabolismus ultrastruktura MeSH
- Fabryho nemoc krev metabolismus patologie MeSH
- galaktosa analýza metabolismus MeSH
- glykosfingolipidy chemie metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- pankreas metabolismus ultrastruktura MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Iron is both an essential and a potentially toxic element, and its systemic homeostasis is controlled by the iron hormone hepcidin. Hepcidin binds to the cellular iron exporter ferroportin, causes its degradation, and thereby diminishes iron uptake from the intestine and the release of iron from macrophages. Given that hepcidin-resistant ferroportin mutant mice show exocrine pancreas dysfunction, we analysed pancreata of aging hepcidin knockout (KO) mice. Hepcidin and Hfe KO mice were compared with wild-type (WT) mice kept on standard or iron-rich diets. Twelve-month-old hepcidin KO mice were subjected to daily minihepcidin PR73 treatment for 1 week. Six-month-old hepcidin KO mice showed cytoplasmic acinar iron overload and mild pancreatitis, together with elevated expression of the iron uptake mediators DMT1 and Zip14. Acinar atrophy, massive macrophage infiltration, fatty changes and pancreas fibrosis were noted in 1-year-old hepcidin KO mice. As an underlying mechanism, 6-month-old hepcidin KO mice showed increased pancreatic oxidative stress, with elevated DNA damage, apoptosis and activated nuclear factor-κB (NF-κB) signalling. Neither iron overload nor pancreatic damage was observed in WT mice fed iron-rich diet or in Hfe KO mice. Minihepcidin application to hepcidin KO mice led to an improvement in general health status and to iron redistribution from acinar cells to macrophages. It also resulted in decreased NF-κB activation and reduced DNA damage. In conclusion, loss of hepcidin signalling in mice leads to iron overload-induced chronic pancreatitis that is not seen in situations with less severe iron accumulation. The observed tissue injury can be reversed by hepcidin supplementation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- MeSH
- acinární buňky metabolismus MeSH
- apoptóza fyziologie MeSH
- chronická pankreatitida etiologie metabolismus patologie MeSH
- cytoplazma metabolismus MeSH
- hepcidiny nedostatek genetika fyziologie MeSH
- makrofágy patologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- oxidační stres fyziologie MeSH
- pankreas ultrastruktura MeSH
- přetížení železem komplikace metabolismus patologie MeSH
- transmisní elektronová mikroskopie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- endokrinní buňky ultrastruktura MeSH
- lidé MeSH
- pankreas anatomie a histologie ultrastruktura MeSH
- Check Tag
- lidé MeSH
- MeSH
- elektronová mikroskopie MeSH
- glukagon imunologie MeSH
- imunohistochemie MeSH
- inzulin imunologie MeSH
- králíci MeSH
- pankreas anatomie a histologie enzymologie ultrastruktura MeSH
- somatostatin imunologie MeSH
- vývody pankreatu patologie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- aurothioglukosa farmakologie MeSH
- myši MeSH
- pankreas účinky léků ultrastruktura MeSH
- Check Tag
- myši MeSH
