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. 1996 Nov 15;98(10):2315–2323. doi: 10.1172/JCI119043

Defective regulation of phosphatidylcholine-specific phospholipases C and D in a kindred with Tangier disease. Evidence for the involvement of phosphatidylcholine breakdown in HDL-mediated cholesterol efflux mechanisms.

M Walter 1, H Reinecke 1, U Gerdes 1, J R Nofer 1, G Höbbel 1, U Seedorf 1, G Assmann 1
PMCID: PMC507682  PMID: 8941649

Abstract

The negative correlation between coronary heart disease and plasma levels of HDL has been attributed to the ability of HDL to take up cellular cholesterol. The HDL3-induced removal of cellular cholesterol was reported to be impaired in fibroblasts from patients with familial HDL deficiency (Tangier disease, TD). In addition, we have recently shown that HDL3 stimulates the hydrolysis of phosphatidylcholine (PC) in cholesterol-loaded fibroblasts. To investigate whether this cell signaling pathway is involved in cholesterol efflux mechanisms, we compared the HDL3-induced PC hydrolysis in normal fibroblasts and in fibroblasts from a TD kindred, in whom the HDL3- and apolipoprotein A-I (apo A-I)-induced mobilization of cellular cholesterol was found to be reduced by 50%. The HDL3-induced formation of phosphatidic acid (PA) via PC-specific phospholipase D (PC-PLD) was markedly reduced by 60-80% in these cells, whereas the formation of diacylglycerol (DG) via PC-specific phospholipase C (PC-PLC) was two- to threefold enhanced. Defective regulation of PC-PLC and PC-PLD was similarly observed in response to apo A-I and endothelin, but not in response to the receptor-independent stimulation of PC hydrolysis by PMA. A Tangier-like PA and DG formation pattern could be induced in normal cells after preincubation with pertussis toxin, suggesting the involvement of a G-protein. The impaired mobilization of radiolabeled cellular cholesterol in TD cells could completely be overcome by increasing the PA levels in the presence of the PA phosphohydrolase inhibitor propranolol. Conversely, the inhibition of PA formation in the presence of 0.3% butanol as well as the inhibition of DG formation in the presence of the PC-PLC inhibitor D 609 reduced the mobilization of cellular cholesterol both in normal and in TD cells. Our data indicate that the coordinate formation of PA and DG via PC-PLD and PC-PLC is essential for efficient cholesterol efflux. The molecular defect in this TD kindred appears to affect an upstream effector of protein kinase C responsible for the G-protein-dependent regulation of PC-specific phospholipases.

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Selected References

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  1. Ambar I., Sokolovsky M. Endothelin receptors stimulate both phospholipase C and phospholipase D activities in different cell lines. Eur J Pharmacol. 1993 Mar 15;245(1):31–41. doi: 10.1016/0922-4106(93)90166-7. [DOI] [PubMed] [Google Scholar]
  2. Assmann G., Capurso A., Smootz E., Wellner U. Apoprotein A metabolism in Tangier disease. Atherosclerosis. 1978 Aug;30(4):321–332. doi: 10.1016/0021-9150(78)90125-9. [DOI] [PubMed] [Google Scholar]
  3. Assmann G., Herbert P. N., Fredrickson D. S., Forte T. Isolation and characterization of an abnormal high density lipoprotein in Tangier Diesase. J Clin Invest. 1977 Jul;60(1):242–252. doi: 10.1172/JCI108761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Assmann G., Simantke O., Schaefer H. E., Smootz E. Characterization of high density lipoproteins in patients heterozygous for Tangier disease. J Clin Invest. 1977 Nov;60(5):1025–1035. doi: 10.1172/JCI108853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Assmann G., Smootz E., Adler K., Capurso A., Oette K. The lipoprotein abnormality in Tangier disease: quantitation of A apoproteins. J Clin Invest. 1977 Mar;59(3):565–575. doi: 10.1172/JCI108672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Assmann G., Smootz E. High density lipoprotein infusion and partial plasma exchange in Tangier disease. Eur J Clin Invest. 1978 Jun;8(3):131–135. doi: 10.1111/j.1365-2362.1978.tb00825.x. [DOI] [PubMed] [Google Scholar]
  7. Bell R. L., Kennerly D. A., Stanford N., Majerus P. W. Diglyceride lipase: a pathway for arachidonate release from human platelets. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3238–3241. doi: 10.1073/pnas.76.7.3238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Billah M. M. Phospholipase D and cell signaling. Curr Opin Immunol. 1993 Feb;5(1):114–123. doi: 10.1016/0952-7915(93)90090-f. [DOI] [PubMed] [Google Scholar]
  9. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  10. Brewer H. B., Jr, Fairwell T., Meng M., Kay L., Ronan R. Human proapoA-ITangier: isolation of proapoA-ITangier and amino acid sequence of the propeptide. Biochem Biophys Res Commun. 1983 Jun 29;113(3):934–940. doi: 10.1016/0006-291x(83)91088-4. [DOI] [PubMed] [Google Scholar]
  11. Brinton E. A., Oram J. F., Chen C. H., Albers J. J., Bierman E. L. Binding of high density lipoprotein to cultured fibroblasts after chemical alteration of apoprotein amino acid residues. J Biol Chem. 1986 Jan 5;261(1):495–503. [PubMed] [Google Scholar]
  12. Chen C. H., Albers J. J. Characterization of proteoliposomes containing apoprotein A-I: a new substrate for the measurement of lecithin: cholesterol acyltransferase activity. J Lipid Res. 1982 Jul;23(5):680–691. [PubMed] [Google Scholar]
  13. Drobnik W., Möllers C., Resink T., Schmitz G. Activation of phosphatidylinositol-specific phospholipase C in response to HDL3 and LDL is markedly reduced in cultured fibroblasts from Tangier patients. Arterioscler Thromb Vasc Biol. 1995 Sep;15(9):1369–1377. doi: 10.1161/01.atv.15.9.1369. [DOI] [PubMed] [Google Scholar]
  14. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  15. Francis G. A., Knopp R. H., Oram J. F. Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier Disease. J Clin Invest. 1995 Jul;96(1):78–87. doi: 10.1172/JCI118082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Galla H. J., Sackmann E. Chemically induced lipid phase separation in model membranes containing charged lipids: a spin label study. Biochim Biophys Acta. 1975 Sep 2;401(3):509–529. doi: 10.1016/0005-2736(75)90249-7. [DOI] [PubMed] [Google Scholar]
  17. Gordon D. J., Rifkind B. M. High-density lipoprotein--the clinical implications of recent studies. N Engl J Med. 1989 Nov 9;321(19):1311–1316. doi: 10.1056/NEJM198911093211907. [DOI] [PubMed] [Google Scholar]
  18. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heider J. G., Boyett R. L. The picomole determination of free and total cholesterol in cells in culture. J Lipid Res. 1978 May;19(4):514–518. [PubMed] [Google Scholar]
  20. Heller M. Phospholipase D. Adv Lipid Res. 1978;16:267–326. doi: 10.1016/b978-0-12-024916-9.50011-1. [DOI] [PubMed] [Google Scholar]
  21. Kaszkin M., Seidler L., Kast R., Kinzel V. Epidermal-growth-factor-induced production of phosphatidylalcohols by HeLa cells and A431 cells through activation of phospholipase D. Biochem J. 1992 Oct 1;287(Pt 1):51–57. doi: 10.1042/bj2870051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lerman A., Edwards B. S., Hallett J. W., Heublein D. M., Sandberg S. M., Burnett J. C., Jr Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991 Oct 3;325(14):997–1001. doi: 10.1056/NEJM199110033251404. [DOI] [PubMed] [Google Scholar]
  23. MacNulty E. E., McClue S. J., Carr I. C., Jess T., Wakelam M. J., Milligan G. Alpha 2-C10 adrenergic receptors expressed in rat 1 fibroblasts can regulate both adenylylcyclase and phospholipase D-mediated hydrolysis of phosphatidylcholine by interacting with pertussis toxin-sensitive guanine nucleotide-binding proteins. J Biol Chem. 1992 Feb 5;267(4):2149–2156. [PubMed] [Google Scholar]
  24. Mautner S. L., Sanchez J. A., Rader D. J., Mautner G. C., Ferrans V. J., Fredrickson D. S., Brewer H. B., Jr, Roberts W. C. The heart in Tangier disease. Severe coronary atherosclerosis with near absence of high-density lipoprotein cholesterol. Am J Clin Pathol. 1992 Aug;98(2):191–198. doi: 10.1093/ajcp/98.2.191. [DOI] [PubMed] [Google Scholar]
  25. Mendez A. J., Oram J. F., Bierman E. L. Protein kinase C as a mediator of high density lipoprotein receptor-dependent efflux of intracellular cholesterol. J Biol Chem. 1991 Jun 5;266(16):10104–10111. [PubMed] [Google Scholar]
  26. Milligan G. Techniques used in the identification and analysis of function of pertussis toxin-sensitive guanine nucleotide binding proteins. Biochem J. 1988 Oct 1;255(1):1–13. doi: 10.1042/bj2550001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Neer E. J. Heterotrimeric G proteins: organizers of transmembrane signals. Cell. 1995 Jan 27;80(2):249–257. doi: 10.1016/0092-8674(95)90407-7. [DOI] [PubMed] [Google Scholar]
  28. Oppenheimer M. J., Oram J. F., Bierman E. L. Up-regulation of high density lipoprotein receptor activity by gamma-interferon associated with inhibition of cell proliferation. J Biol Chem. 1988 Dec 25;263(36):19318–19323. [PubMed] [Google Scholar]
  29. Oram J. F., Brinton E. A., Bierman E. L. Regulation of high density lipoprotein receptor activity in cultured human skin fibroblasts and human arterial smooth muscle cells. J Clin Invest. 1983 Nov;72(5):1611–1621. doi: 10.1172/JCI111120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pai J. K., Siegel M. I., Egan R. W., Billah M. M. Phospholipase D catalyzes phospholipid metabolism in chemotactic peptide-stimulated HL-60 granulocytes. J Biol Chem. 1988 Sep 5;263(25):12472–12477. [PubMed] [Google Scholar]
  31. Pappu A. S., Hauser G. Propranolol-induced inhibition of rat brain cytoplasmic phosphatidate phosphohydrolase. Neurochem Res. 1983 Dec;8(12):1565–1575. doi: 10.1007/BF00964158. [DOI] [PubMed] [Google Scholar]
  32. Phillips M. C., Johnson W. J., Rothblat G. H. Mechanisms and consequences of cellular cholesterol exchange and transfer. Biochim Biophys Acta. 1987 Jun 24;906(2):223–276. doi: 10.1016/0304-4157(87)90013-x. [DOI] [PubMed] [Google Scholar]
  33. Reinhart W. H., Gössi U., Bütikofer P., Ott P., Sigrist H., Schatzmann H. J., Lutz H. U., Straub P. W. Haemolytic anaemia in analpha-lipoproteinaemia (Tangier disease): morphological, biochemical, and biophysical properties of the red blood cell. Br J Haematol. 1989 Jun;72(2):272–277. doi: 10.1111/j.1365-2141.1989.tb07694.x. [DOI] [PubMed] [Google Scholar]
  34. Robenek H., Schmitz G. Abnormal processing of Golgi elements and lysosomes in Tangier disease. Arterioscler Thromb. 1991 Jul-Aug;11(4):1007–1020. doi: 10.1161/01.atv.11.4.1007. [DOI] [PubMed] [Google Scholar]
  35. Rogler G., Trümbach B., Klima B., Lackner K. J., Schmitz G. HDL-mediated efflux of intracellular cholesterol is impaired in fibroblasts from Tangier disease patients. Arterioscler Thromb Vasc Biol. 1995 May;15(5):683–690. doi: 10.1161/01.atv.15.5.683. [DOI] [PubMed] [Google Scholar]
  36. Schaefer E. J., Blum C. B., Levy R. I., Jenkins L. L., Alaupovic P., Foster D. M., Brewer H. B., Jr Metabolism of high-density lipoprotein apolipoproteins in Tangier disease. N Engl J Med. 1978 Oct 26;299(17):905–910. doi: 10.1056/NEJM197810262991701. [DOI] [PubMed] [Google Scholar]
  37. Schmitz G., Assmann G., Robenek H., Brennhausen B. Tangier disease: a disorder of intracellular membrane traffic. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6305–6309. doi: 10.1073/pnas.82.18.6305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schmitz G., Fischer H., Beuck M., Hoecker K. P., Robenek H. Dysregulation of lipid metabolism in Tangier monocyte-derived macrophages. Arteriosclerosis. 1990 Nov-Dec;10(6):1010–1019. doi: 10.1161/01.atv.10.6.1010. [DOI] [PubMed] [Google Scholar]
  39. Serfaty-Lacrosniere C., Civeira F., Lanzberg A., Isaia P., Berg J., Janus E. D., Smith M. P., Jr, Pritchard P. H., Frohlich J., Lees R. S. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis. 1994 May;107(1):85–98. doi: 10.1016/0021-9150(94)90144-9. [DOI] [PubMed] [Google Scholar]
  40. Takuwa N., Takuwa Y., Rasmussen H. A tumour promoter, 12-O-tetradecanoylphorbol 13-acetate, increases cellular 1,2-diacylglycerol content through a mechanism other than phosphoinositide hydrolysis in Swiss-mouse 3T3 fibroblasts. Biochem J. 1987 May 1;243(3):647–653. doi: 10.1042/bj2430647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Walter M., Gerdes U., Seedorf U., Assmann G. The high density lipoprotein- and apolipoprotein A-I-induced mobilization of cellular cholesterol is impaired in fibroblasts from Tangier disease subjects. Biochem Biophys Res Commun. 1994 Nov 30;205(1):850–856. doi: 10.1006/bbrc.1994.2742. [DOI] [PubMed] [Google Scholar]
  42. Walter M., Kerber S., Fechtrup C., Seedorf U., Breithardt G., Assmann G. Characterization of atherosclerosis in a patient with familial high-density lipoprotein deficiency. Atherosclerosis. 1994 Oct;110(2):203–208. doi: 10.1016/0021-9150(94)90205-4. [DOI] [PubMed] [Google Scholar]
  43. Walter M., Reinecke H., Nofer J. R., Seedorf U., Assmann G. HDL3 stimulates multiple signaling pathways in human skin fibroblasts. Arterioscler Thromb Vasc Biol. 1995 Nov;15(11):1975–1986. doi: 10.1161/01.atv.15.11.1975. [DOI] [PubMed] [Google Scholar]
  44. Yavin E. Regulation of phospholipid metabolism in differentiating cells from rat brain cerebral hemispheres in culture. Patterns of acetylcholine phosphocholine, and choline phosphoglycerides labeling from (methyl-14C)choline. J Biol Chem. 1976 Mar 10;251(5):1392–1397. [PubMed] [Google Scholar]
  45. van Blitterswijk W. J., Hilkmann H., de Widt J., van der Bend R. L. Phospholipid metabolism in bradykinin-stimulated human fibroblasts. II. Phosphatidylcholine breakdown by phospholipases C and D; involvement of protein kinase C. J Biol Chem. 1991 Jun 5;266(16):10344–10350. [PubMed] [Google Scholar]
  46. von Eckardstein A., Funke H., Walter M., Altland K., Benninghoven A., Assmann G. Structural analysis of human apolipoprotein A-I variants. Amino acid substitutions are nonrandomly distributed throughout the apolipoprotein A-I primary structure. J Biol Chem. 1990 May 25;265(15):8610–8617. [PubMed] [Google Scholar]

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