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Hepatocyte nuclear factor 1A deficiency causes hemolytic anemia in mice by altering erythrocyte sphingolipid homeostasis.
von Wnuck Lipinski, Karin; Weske, Sarah; Keul, Petra; Peters, Susann; Baba, Hideo A; Heusch, Gerd; Gräler, Markus H; Levkau, Bodo.
Afiliação
  • von Wnuck Lipinski K; Institute for Pathophysiology, West German Heart and Vascular Center and.
  • Weske S; Institute for Pathophysiology, West German Heart and Vascular Center and.
  • Keul P; Institute for Pathophysiology, West German Heart and Vascular Center and.
  • Peters S; Institute for Pathophysiology, West German Heart and Vascular Center and.
  • Baba HA; Institute for Pathology, University Hospital Essen, Essen, Germany.
  • Heusch G; Institute for Pathophysiology, West German Heart and Vascular Center and.
  • Gräler MH; Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care and.
  • Levkau B; Center for Molecular Biomedicine, University Hospital Jena, Jena, Germany.
Blood ; 130(25): 2786-2798, 2017 12 21.
Article em En | MEDLINE | ID: mdl-29109103
The hepatocyte nuclear factor (HNF) family regulates complex networks of metabolism and organ development. Human mutations in its prototypical member HNF1A cause maturity-onset diabetes of the young (MODY) type 3. In this study, we identified an important role for HNF1A in the preservation of erythrocyte membrane integrity, calcium homeostasis, and osmotic resistance through an as-yet unrecognized link of HNF1A to sphingolipid homeostasis. HNF1A-/- mice displayed microcytic hypochromic anemia with reticulocytosis that was partially compensated by avid extramedullary erythropoiesis at all erythroid stages in the spleen thereby excluding erythroid differentiation defects. Morphologically, HNF1A-/- erythrocytes resembled acanthocytes and displayed increased phosphatidylserine exposure, high intracellular calcium, and elevated osmotic fragility. Sphingolipidome analysis by mass spectrometry revealed substantial and tissue-specific sphingolipid disturbances in several tissues including erythrocytes with the accumulation of sphingosine as the most prominent common feature. All HNF1A-/- erythrocyte defects could be simulated by exposure of wild-type (WT) erythrocytes to sphingosine in vitro and attributed in part to sphingosine-induced suppression of the plasma-membrane Ca2+-ATPase activity. Bone marrow transplantation rescued the anemia phenotype in vivo, whereas incubation with HNF1A-/- plasma increased the osmotic fragility of WT erythrocytes in vitro. Our data suggest a non-cell-autonomous erythrocyte defect secondary to the sphingolipid changes caused by HNF1A deficiency. Transcriptional analysis revealed 4 important genes involved in sphingolipid metabolism to be deregulated in HNF1A deficiency: Ormdl1, sphingosine kinase-2, neutral ceramidase, and ceramide synthase-5. The considerable erythrocyte defects in murine HNF1A deficiency encourage clinical studies to explore the hematological consequences of HNF1A deficiency in human MODY3 patients.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esfingolipídeos / Fator 1-alfa Nuclear de Hepatócito / Homeostase / Anemia Hemolítica Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals Idioma: En Revista: Blood Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esfingolipídeos / Fator 1-alfa Nuclear de Hepatócito / Homeostase / Anemia Hemolítica Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals Idioma: En Revista: Blood Ano de publicação: 2017 Tipo de documento: Article