Systemic ceramide accumulation leads to severe and varied pathological consequences
Systemic ceramide accumulation leads to severe and varied pathological consequences
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DOI：
10.1002/emmm.201202301
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发表时间：
2013-06-01
影响因子：
11.1
通讯作者：
Medin, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Alayoubi, Abdulfatah M.;Wang, James C. M.;Medin, Jeffrey A.
法伯病（Farber disease， FD）是一种严重的遗传性脂质代谢疾病，其特征是溶酶体酸性神经酰胺酶（ACDase）活性不足，导致神经酰胺积聚。神经酰胺及其代谢物在细胞凋亡和增殖中起作用。我们将在人类FD患者中发现的单核苷酸突变引入小鼠Asah1基因中，以产生第一个全身性ACDase缺乏症模型。纯合子Asah1P361R/P361R动物出现ACDase缺陷，神经酰胺积累，出现FD表现，在7-13周内死亡。机制上，MCP-1水平升高，组织中充满脂质巨噬细胞。单次注射人类acase编码慢载体治疗新生儿，可以通过增强生长、减少神经酰胺、减少细胞浸润和延长寿命来降低疾病的严重程度。这种ACDase缺乏模型为FD的病理生理学以及ACDase、神经酰胺和相关鞘脂在细胞信号传导和生长中的作用提供了新的见解，并促进了治疗的发展。参见随附文章http://dx.doi.org/10.1002/emmm.201302781
Farber disease (FD) is a severe inherited disorder of lipid metabolism characterized by deficient lysosomal acid ceramidase (ACDase) activity, resulting in ceramide accumulation. Ceramide and metabolites have roles in cell apoptosis and proliferation. We introduced a single-nucleotide mutation identified in human FD patients into the murine Asah1 gene to generate the first model of systemic ACDase deficiency. Homozygous Asah1P361R/P361R animals showed ACDase defects, accumulated ceramide, demonstrated FD manifestations and died within 7-13 weeks. Mechanistically, MCP-1 levels were increased and tissues were replete with lipid-laden macrophages. Treatment of neonates with a single injection of human ACDase-encoding lentivector diminished the severity of the disease as highlighted by enhanced growth, decreased ceramide, lessened cellular infiltrations and increased lifespans. This model of ACDase deficiency offers insights into the pathophysiology of FD and the roles of ACDase, ceramide and related sphingolipids in cell signaling and growth, as well as facilitates the development of therapy. See accompanying article http://dx.doi.org/10.1002/emmm.201302781