Worgall Tilla S
Department of Pathology, Pediatrics and Institute of Human Nutrition, Columbia University, BB 457, New York 10032, USA.
Curr Opin Clin Nutr Metab Care. 2009 Mar;12(2):105-9. doi: 10.1097/mco.0b013e32832595b7.
Expression of defective cystic fibrosis transmembrane conductance regulator (CFTR), the cause for cystic fibrosis, affects fatty acid, cholesterol and sphingolipid metabolism. This review summarizes recent observations and evaluates current understanding of mechanisms.
Recent observations implicate CFTR, in addition to known effects on fatty acid and cholesterol metabolism, in the regulation of sphingolipid metabolism and suggest that this pathway is relevant to inflammation and infection. A common mechanism on how CFTR affects such a wide spectrum of lipid classes is currently not known. One mechanism for low linoleic acid, amenable to inhibition by docosahexaenoic acid, is increased metabolism in the n-6 fatty acid pathway. Accumulation of free cholesterol in distinct perinuclear compartments, reversible by overexpression of rab9, suggests that cystic fibrosis and the lysosomal storage disease Niemann-Pick-C could share similar cell signaling defects, in addition to increased cAMP signaling and sterol-regulatory element binding protein (SREBP) expression that affect cholesterol metabolism. Novel is the recognition that CFTR modulates ceramide mass and uptake of sphingosine-1- phosphate. Experiments in different cystic fibrosis-mouse models, although not able to establish whether ceramide mass is increased or decreased, suggest that normalization of ceramide decreases infection and selected parameters of inflammation, of relevance to the complex phenotype that characterizes cystic fibrosis.
Expression of defective CFTR has profound effects on fatty acid, cholesterol and sphingolipid metabolism, for which mechanisms are currently poorly understood. Recent studies in different cystic fibrosis models suggest a causal relationship between altered ceramide mass and increased inflammation and susceptibility to infection. Studies in cystic fibrosis knockout mouse models suggest that normalization of ceramide decreases infection and inflammation. Studies that evaluate the diagnostic and clinical relevance of sphingolipids in patients with cystic fibrosis are needed.
囊性纤维化跨膜传导调节因子（CFTR）功能缺陷是囊性纤维化的病因，其表达会影响脂肪酸、胆固醇和鞘脂代谢。本综述总结了近期的观察结果并评估了目前对相关机制的理解。
近期观察结果表明，CFTR除了对脂肪酸和胆固醇代谢有已知影响外，还参与鞘脂代谢的调节，并提示该途径与炎症和感染相关。目前尚不清楚CFTR如何影响如此广泛的脂质种类的共同机制。低亚油酸的一种机制（可被二十二碳六烯酸抑制）是n-6脂肪酸途径中的代谢增加。游离胆固醇在不同的核周区室中积累，通过rab9的过表达可逆转，这表明囊性纤维化与溶酶体贮积病尼曼-匹克C型可能存在相似的细胞信号缺陷，此外还存在影响胆固醇代谢的环磷酸腺苷（cAMP）信号增加和固醇调节元件结合蛋白（SREBP）表达增加的情况。新发现的是CFTR调节神经酰胺总量和鞘氨醇-1-磷酸的摄取。在不同的囊性纤维化小鼠模型中进行的实验，虽然无法确定神经酰胺总量是增加还是减少，但表明神经酰胺的正常化可降低感染和某些炎症参数，这与囊性纤维化的复杂表型相关。
缺陷型CFTR的表达对脂肪酸、胆固醇和鞘脂代谢有深远影响，目前对其机制了解甚少。近期在不同囊性纤维化模型中的研究表明，神经酰胺总量改变与炎症增加和感染易感性之间存在因果关系。在囊性纤维化基因敲除小鼠模型中的研究表明，神经酰胺的正常化可降低感染和炎症。需要开展评估鞘脂在囊性纤维化患者中的诊断和临床相关性的研究。
