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Hepatocyte nuclear factor 1A deficiency causes hemolytic anemia in mice by altering erythrocyte sphingolipid homeostasis
Blood ( IF 20.3 ) Pub Date : 2017-12-21 , DOI: 10.1182/blood-2017-03-774356
Karin von Wnuck Lipinski 1 , Sarah Weske 1 , Petra Keul 1 , Susann Peters 1 , Hideo A. Baba 2 , Gerd Heusch 1 , Markus H. Gräler 3, 4 , Bodo Levkau 1
Affiliation  

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.

中文翻译:

肝细胞核因子1A缺乏通过改变红细胞鞘脂稳态导致小鼠溶血性贫血

肝细胞核因子 (HNF) 家族调节代谢和器官发育的复杂网络。其原型成员 HNF1A 中的人类突变导致年轻 (MODY) 3 型成熟型糖尿病。在这项研究中,我们确定了 HNF1A 在保存红细胞膜完整性、钙稳态和渗透阻力方面的重要作用,尚未认识到 HNF1A 与鞘脂稳态的联系。HNF1A-/- 小鼠表现出具有网织红细胞增多症的小细胞性低色素性贫血,在脾脏的所有红细胞阶段都被狂热的髓外红细胞生成部分补偿,从而排除了红细胞分化缺陷。在形态学上,HNF1A-/- 红细胞类似于棘红细胞,并显示出增加的磷脂酰丝氨酸暴露、高细胞内钙和升高的渗透脆性。通过质谱法进行的鞘脂组分析揭示了包括红细胞在内的几种组织中大量的组织特异性鞘脂紊乱,其中鞘氨醇的积累是最突出的共同特征。所有 HNF1A-/- 红细胞缺陷都可以通过将野生型 (WT) 红细胞在体外暴露于鞘氨醇中来模拟,部分原因是鞘氨醇诱导的质膜 Ca2+-ATPase 活性受到抑制。骨髓移植在体内挽救了贫血表型,而与 HNF1A-/- 血浆孵育在体外增加了 WT 红细胞的渗透脆性。我们的数据表明继发于 HNF1A 缺乏引起的鞘脂变化的非细胞自主性红细胞缺陷。转录分析显示,在 HNF1A 缺乏症中,涉及鞘脂代谢的 4 个重要基因失调:Ormdl1、鞘氨醇激酶-2、中性神经酰胺酶和神经酰胺合酶-5。小鼠 HNF1A 缺乏症中相当大的红细胞缺陷鼓励临床研究探索人类 MODY3 患者 HNF1A 缺乏症的血液学后果。
更新日期:2017-12-21
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