Kacher Yaacov, Golan Avner, Pewzner-Jung Yael, Futerman Anthony H
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Blood Cells Mol Dis. 2007 Jul-Aug;39(1):124-9. doi: 10.1016/j.bcmd.2007.03.005. Epub 2007 May 7.
We have recently shown that phosphatidylcholine (PC) metabolism is altered in a macrophage model of Gaucher disease. We now demonstrate that treatment of macrophages with conduritol-B-epoxide (CBE), a glucocerebrosidase inhibitor, results in elevated activity of CTP:phosphocholine cytidylyltransferase (CCT), the rate-limiting enzyme in the pathway of PC biosynthesis. Furthermore, we provide evidence for a role for CCT in Gaucher macrophage growth by using macrophages derived from a genetically modified mouse which lacks a specific CCT isoform, CCTalpha, in macrophages. Upon CBE-treatment, macrophage size, analyzed by microscopy and by FACS, was significantly increased in macrophages from control mice, but did not increase, or increased to a much lower extent, in CCTalpha-/- macrophages. Together, these results suggest that the increase in PC biosynthesis is mediated via CCTalpha, and suggests a possible role for macrophage CCTalpha in Gaucher disease pathology.
我们最近发现，在戈谢病的巨噬细胞模型中，磷脂酰胆碱（PC）代谢发生了改变。我们现在证明，用葡萄糖脑苷脂酶抑制剂环醇-B-环氧化物（CBE）处理巨噬细胞，会导致CTP：磷酸胆碱胞苷转移酶（CCT）活性升高，CCT是PC生物合成途径中的限速酶。此外，我们通过使用源自基因改造小鼠的巨噬细胞提供了证据，该小鼠巨噬细胞缺乏特定的CCT亚型CCTα。经CBE处理后，通过显微镜和流式细胞术分析，对照小鼠巨噬细胞的大小显著增加，但在CCTα-/-巨噬细胞中没有增加或增加幅度小得多。总之，这些结果表明PC生物合成的增加是通过CCTα介导的，并提示巨噬细胞CCTα在戈谢病病理中可能发挥作用。
