ACTIVATION OF PHOSPHATIDYLINOSITOL-SPECIFIC PHOSPHOLIPASE-C IN RESPONSE TO HDL(3) AND LDL IS MARKEDLY REDUCED IN CULTURED FIBROBLASTS FROM TANGIER PATIENTS

We compared HDL(3)- 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 disor der of cellular lipid and lipoprotein metabolism. In several cell type s HDL and LDL activate a currently unknown isoform of phosphatidylinos itol-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 HDL(3) or LDL resulted in a significantly reduced accumulation of inositol phosphate s and 1,2-diacylglycerol formation. Furthermore, in Tangier fibroblast s both lipoproteins failed to mobilize calcium from internal pools, an d the cytosol-to-membrane redistribution of protein kinase C (in both the alpha and epsilon isoforms) was markedly reduced. Thus, the data i ndicate an impaired PI-PLC activation in response to lipoproteins in T angier fibroblasts.