The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice.
The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice.
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DOI：
10.1016/j.jaci.2019.06.041
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Lambrecht BN
中科院分区：
文献类型：
--
作者：
Debeuf N;Zhakupova A;Steiner R;Van Gassen S;Deswarte K;Fayazpour F;Van Moorleghem J;Vergote K;Pavie B;Lemeire K;Hammad H;Hornemann T;Janssens S;Lambrecht BN
哮喘的全基因组关联研究已经反复发现不同人群中ORM(酵母样蛋白异构体3 （ORMDL3）基因的单核苷酸多态性。虽然酵母中的orm同源物是众所周知的鞘脂（SL）合成抑制剂，但哺乳动物ORMDL3是否以及如何调节鞘脂代谢以及改变的鞘脂合成是否与哮喘风险有因果关系尚不清楚。为了研究ORMDL3在体内SL代谢和过敏性哮喘ORMDL3 - lacz报告小鼠中的作用，我们将ORMDL3 -/-基因缺失和过表达ORMDL3 Tg/wt的小鼠暴露于与生理相关的空气过敏原（如尘螨或交替菌）中诱导实验性哮喘。采用质谱法进行鞘脂组学研究，测量气道嗜酸性粒细胞、Th2细胞因子产生、Ig合成、气道重塑和支气管高反应性。与对照组相比，HDM刺激显著增加了HDM致敏小鼠肺部的总鞘脂。在Ormdl3Tg/wt小鼠中，过敏原诱导的肺神经酰胺增加明显减少，而总鞘脂水平不受影响。相反，在肝脏和血清中，Ormdl3-/-小鼠的总鞘脂包括神经酰胺增加，而Ormdl3 tg /wt小鼠的总鞘脂包括神经酰胺降低。这种差异与过敏原暴露无关。尽管有这些变化，在几种实验性哮喘模型中，野生型、Ormdl3 tg /wt和Ormdl3-/-小鼠之间哮喘的所有特征是相同的。ORMDL3调节全身神经酰胺水平，但基因上干扰ORMDL3。表达不导致实验性哮喘的改变。ORMDL3调节全身神经酰胺水平，但基因干扰ORMDL3的表达不会导致实验性哮喘的改变。
Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM-homologues in yeast are well-known inhibitors of sphingolipid (SL) synthesis, it is still unclear whether and how mammalian ORMDL3 regulates SL metabolism and whether altered SL synthesis would be causally related to asthma risk. To examine the in vivo role of ORMDL3 in SL metabolism and allergic asthma Ormdl3-LacZ reporter mice, gene deficient Ormdl3-/- and overexpressing Ormdl3 Tg/wt mice were exposed to physiologically relevant aeroallergens such as house dust mite or Alternaria alternata to induce experimental asthma. Mass spectrometry based sphingolipidomics was performed, and airway eosinophilia, Th2 cytokine production, Ig synthesis, airway remodeling and bronchial hyperreactivity measured. HDM challenge significantly increased total sphingolipids in the lung of HDM-sensitized mice compared to controls. In Ormdl3Tg/wt mice, the allergen-induced increase in lung ceramides was significantly reduced, whereas total sphingolipid levels were not affected. Conversely, in liver and serum, total sphingolipids including ceramides were increased in Ormdl3-/- mice, while they were lowered in Ormdl3Tg/wt mice. This difference was independent of allergen exposure. Despite these changes, all features of asthma were identical between wildtype, Ormdl3Tg/wt and Ormdl3-/- mice, across several models of experimental asthma. ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3. expression does not result in altered experimental asthma. ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma.
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影响因子：
16.6
作者：
Ha, Sung Gil;Ge, Xiao Na;Bahaie, Nooshin S.;Kang, Bit Na;Rao, Amrita;Rao, Savita P.;Sriramarao, P.
通讯作者：
Sriramarao, P.
影响因子：
30.5
作者：
Lambrecht, Bart N.;Hammad, Hamida
通讯作者：
Hammad, Hamida
影响因子：
158.5
作者：
Bouzigon, Emmanuelle;Corda, Eve;Demenais, Florence
通讯作者：
Demenais, Florence
DOI：
10.1016/j.bbalip.2005.08.006
发表时间：
2005-10-15
影响因子：
4.8
作者：
Hojjati, MR;Li, ZQ;Jiang, XC
通讯作者：
Jiang, XC
影响因子：
9.9
作者：
Atkinson, Derek;Glumac, Jelena Nikodinovic;Jordanova, Albena
通讯作者：
Jordanova, Albena