Activation of phosphatidylinositol-specific phospholipase C in response to HDL3 and LDL is markedly reduced in cultured fibroblasts from Tangier patients.
We compared HDL3- and LDL-induced signal transduction in normal and Tangier fibroblasts to elucidate whether impaired signal transduction responses to lipoproteins might contribute to disturbed cellular lipid and lipoprotein metabolism in Tangier disease, a rare autosomal disorder of cellular lipid and lipoprotein metabolism. In several cell types HDL and LDL activate a currently unknown isoform of phosphatidylinositol-specific phospholipase C (PI-PLC) that results in the generation of 1,2-diacylglycerol and inositol 1,4,5-trisphosphate. Compared with normal fibroblasts, Tangier fibroblasts stimulated with HDL3 or LDL resulted in a significantly reduced accumulation of inositol phosphates and 1,2-diacylglycerol formation. Furthermore, in Tangier fibroblasts both lipoproteins failed to mobilize calcium from internal pools, and the cytosol-to-membrane redistribution of protein kinase C (in both the alpha and epsilon isoforms) was markedly reduced. Thus, the data indicate an impaired PI-PLC activation in response to lipoproteins in Tangier fibroblasts.
Drobnik
W
W
Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany.
Möllers
C
C
Resink
T
T
Schmitz
G
G
D000328:Adult; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008074:Lipoproteins / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D053440:Lipoproteins, HDL3; D008297:Male; D008875:Middle Aged; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013631:Tangier Disease / Q000201:enzymology*
C011439:1,2-diacylglycerol; D004075:Diglycerides; D007295:Inositol Phosphates; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase