Changes in macrophage morphology in a Gaucher disease model are dependent on CTP:phosphocholine cytidylyltransferase α

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 glucocerebrosiclase 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, CCT alpha, 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 CCT alpha-/- macrophages. Together, these results suggest that the increase in PC biosynthesis is mediated via CCT alpha, and suggests a possible role for macrophage CCT alpha in Gaucher disease pathology. (c) 2007 Elsevier Inc. All rights reserved.