A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr-/- mice
A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr-/- mice
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膜脂失衡在 cftr-/- 小鼠囊性纤维化的表型表达中起作用
DOI：
10.1073/pnas.96.24.13995
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发表时间：
1999-11-23
影响因子：
11.1
通讯作者：
Alvarez, JG
中科院分区：
文献类型：
--
作者：
Freedman, SD;Katz, MH;Alvarez, JG
囊性纤维化（CF）患者血浆中存在必需脂肪酸代谢缺陷，但其病因和在疾病表达中的作用尚不清楚。本研究的目的是确定脂肪酸代谢的改变是否特异于CF调节的器官，以及它们是否在疾病的表达中起作用。在cftr（-/-）小鼠的回肠、胰腺和肺中发现了膜脂质失衡，其特征在于磷脂结合的花生四烯酸增加和磷脂结合的二十二碳六烯酸（DHA）减少。在CF病理影响的器官（包括肺、胰腺和回肠）中观察到这种脂质失衡，并且这种脂质失衡不是继发于DHA的肠吸收或肝脏生物合成受损。作为概念证明，对cftr（-/-）小鼠口服DHA可纠正这种脂质失衡并逆转观察到的病理表现。这些结果强烈表明，CF的某些表型表现可能是由磷脂结合花生四烯酸和二十二碳六烯酸水平的可补救改变引起的。
A deficiency in essential fatty acid metabolism has been reported in plasma from patients with cystic: fibrosis (CF), However, its etiology and role in the expression of disease is unknown. The objective of this study was to determine whether alterations in fatty acid metabolism are specific to CF-regulated organs and whether they play a role in the expression of disease. A membrane lipid imbalance was found in ileum, pancreas, and lung from cftr(-/-) mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid (DHA). This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA. As proof of concept, oral administration of DHA to cftr(-/-) mice corrected this lipid imbalance and reversed the observed pathological manifestations. These results strongly suggest that certain phenotypic manifestations of CF may result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels.