Abstract
It is well known that acute and chronic inflammatory reactions are accompanied by markedly decreased concentrations of plasma total cholesterol. However, the mechanisms underlying this hypocholesterolemia are not yet completely understood. To explore the question of whether an increased serum activity of secretory group IIA phospholipase A2 (sPLA2) may contribute to the development of hypocholesterolemia during inflammation, the lipids and lipoprotein patterns in the plasma of transgenic mice overexpressing the human sPLA2 gene were studied and compared with those of nontransgenic controls. The mean plasma enzyme activities determined by using [14C]-oleate labeled Escherichia coli-membranes were found to be 331 ± 262 U/l in transgenic mice while the catalytic activity in plasma of controls was below the analytical sensitivity of the assay (0.5 U/l). Compared to nontransgenic littermates, sPLA2-transgenic mice exhibited significantly lower plasma concentrations of total cholesterol (2.53 ± 0.37 mmol/l vs. 3.49 ± 0.44 mmol/l, p < 0.0001). The reduction of total cholesterol was due to decreased HDL and LDL cholesterol levels (1.21 ± 0.10 mmol/l vs. 1.78 ± 0.37 mmol/l, and 0.28 ± 0.02 mmol/l vs. 0.69 ± 0.23 mmol/l, respectively, p < 0.05). The analysis of lipoprotein composition indicated that the LDL of transgenic mice were selectively depleted in free and esterified cholesterol, whereas HDL of the two animal groups contained comparable percentages of cholesterol. The triglycerides were significantly enriched in LDL and HDL, but tended to be less in VLDL of transgenic mice. In conclusion, the results of the study have demonstrated that the expression of sPLA2 may influence the metabolism of lipoproteins, possibly contributing to the development of hypocholesterolemia during inflammation.
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REFERENCES
WINDLER, E., U. EWERS-GRABOW, J. THIERY, A. WALLI, D. SEIDEL, and H. GRETEN. 1994. The prognostic value of hypocholesterolemia in hospitalized patients. Clin. Invest. 72:939-943.
VADAS, P., and W. PRUZANSKI. 1986. Role of secretory phospholipase A2 in the pathobiology of diseases. Lab. Invest. 55:391-404.
NEVALAINEN, T. J. Serum phospholipase A2 in inflammatory diseases. 1993. Clin. Chem. 39:2453-2459.
VADAS, P., and W. PRUZANSKI. 1984. Role of extracellular phospholipase A2 in inflammation. Adv. Inflammation Res. 7:51-59.
PRUZANSKI, W., and P. VADAS. 1991. Phospholipase A2-A mediator between proximal and distal effectors of inflammation. Immunol. Today 12:143-146.
YAMASHITA, S., M. OGAWA, K. SAKAMOTO, T. ABE, H. ARAKAWA, and J. YAMASHITA. 1994. Elevation of serum phospholipase A2 levels in patients with advanced cancer. Clin. Chim. Acta 228:91-99.
BAMBERGER, M., S. LUND-KATZ, M. C. PHILLIPS, and G. H. ROTHBLAT. 1985. Mechanism of the hepatic lipase induced accumulation of high density lipoprotein cholesterol by cells in culture. Biochemistry 24:3693-3701.
GORSHKOVA, I., M. MENSCHIKOWSKI, and W. JAROSS. 1996. Alterations in the physiochemical characteristics of low and high density lipoproteins after lipolysis with phospholipase A2. A spin label study. Biochim. Biophys. Acta. 1300:103-107.
BAMBERGER, M., J. M. GLICK, and G. H. ROTHBLAT. 1983. Hepatic lipase stimulates the uptake of high density lipoprotein cholesterol by hepatoma cells. J. Lipid Res. 24:869-876.
AVIRAM, M., and I. MAOR. 1992. Phospholipase A2-modified LDL is taken up at enhanced rate by macrophages. Biochim. Biophys. Acta 185:465-472.
MENSCHIKOWSKI, M., P. LATTKE, S. BERGMANN, and W. JAROSS. 1995. Exposure of macrophages to PLA2-modified lipoproteins leads to cellular lipid accumulations. Anal. Cell. Pathol. 9:113-117.
KLEINMAN, Y., E. S. KRUL, M. BURNES, W. ARONSON, B. PFLEGER, and G. SCHONFELD. 1988. Lipolysis of LDL with phospholipase A2 alters the expression of selected apoB-100 epitopes and the interaction of LDL with cells. J. Lipid Res. 29:729-743.
COLLET, X., P. PERRET, F. COLLET, F. HULLIN, H. CHAP, and L. DOUSTE-BLAZY. 1988. Uptake of HDL unesterified and esterified cholesterol by human endothelial cells. Modulation by HDL phospholipolysis and cell cholesterol content. Biochim. Biophys. Acta 958:81-92.
COLLET, X., B. P. PERRET, G. SIMARD, C. VIEU, and L. DOUSTE-BLAZY. 1990. Behaviour of phospholipase-modified HDL towards cultured hepatocytes. I. Enhanced transfers of HDL sterols and apoproteins. Biochim. Biophys. Acta 1043:301-310.
LABEQUE, R., C. J. P. MULLON, J. P. M. FERREIRA, R. S. LEES, and R. LANGER. 1993. Enzymatic modification of plasma low density lipoproteins in rabbits: A potential treatment for hypercholesterolemia. Proc. Natl. Acad. Sci. 90:3476-3480.
SHEFER, S. D., R. G. PAYNE, and R. LANGER. 1993. Design of a biomedical reactor for plasma low density lipoprotein removal. Biotechnol. Bioeng. 42:1252-1262.
SHEFER, S. D., J. P. M. FERREIRA, C. J. P. MULLON, and R. LANGER. 1993. Physiological response to the extracorporal removal of low density lipoprotein in rabbits: Efficacy and safety. Int. J. Artif. Organs 15:218-228.
DE BEER, F. C., M. C. DE BEER, D. R. VAN DER WESTHUYZEN, L. W. CASTELLANI, A. J. LUSIS, M. E. SWANSON, and D. S. GRASS. 1997. Secretory non-pancreatic phospholipase A2: Influence on lipoprotein metabolism. J. Lipid Res. 38:2232-2239.
GRASS, D. S., R. H. FELKNER, M. Y. CHIANG, R. E. WALLACE, T. J. NEVALAINEN, C. F. BENNETT, and M. E. SWANSON. 1996. Expression of human group II PLA2 in transgenic mice results in epidermal hyperplasia in the absence of inflammatory infiltrate. J. Clin. Invest. 97:2233-2241.
CROWL, R., C. STONER, T. STOLLER, Y. C. PAN, and R. CONROY. 1990. Isolation and characterization of cDNA clones from human placenta coding for phospholipase A2. Adv. Exp. Med. Biol. 279:173-184.
KRAMER, R. M., C. HESSION, B. JOHANSEN, P. HAYES, P. MCGRAY, E. P. CHOW, R. TIZARD, and R. B. Pepinsky. 1989. Structure and properties of a human non-pancreatic phospholipase A2. J. Biol. Chem. 264:5768-5775.
SEILHAMER, J. J., W. PRUZANSKI, P. VADAS, S. PLANT, J. A. MILLER, J. KLOSS, and L. K. JOHNSON. 1989. Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid. J. Biol. Chem. 264:5335-5338.
AUFENANGER, J., W. ZIMMER, and R. KATTERMANN. 1993. Characteristics and clinical application of a radiometric Escherichia coli-based phospholipase A2 assay modified for serum analysis. Clin. Chem. 39:605-613.
LOWRY, O. H., N. J. ROSENBROUGH, A. L. FARR, and R. J. RANDALL. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265-275.
PIETZSCH, J., S. SUBAT, S. NITZSCHE, W. LEONHARDT, K. U. SCHENTKE, and M. HANEFELD. 1995. Very fast ultracentrifugation of serum lipoproteins: Influence on lipoprotein separation and composition. Biochim. Biophys. Acta 1254:77-88.
CAMUS, M. C., R. AUBERT, F. BOURGEOIS, J. HERZO, A. ALEXIU, and D. LEMONNIER. 1988. Serum lipoprotein profiles of the genetically obese ob/ob mouse. Biochim. Biophys. Acta 961:53-64.
KENNEDY, B. P., P. PAYETTE, J. MUDGETT, P. VADAS, W. PRUZANSKI, M. KWAN, C. TANG, D. E. RANCOURT, and W. A. CROMLISH. 1995. A natural disruption of the secretory group II phospholipase A2gene in inbred mouse strains. J. Biol. Chem. 270:22378-22385.
SAMMALKORPI, K., V. VLATONEN, Y. KERTTUBA, E. NIKKILA, and M. R. TASKINEN. 1988. Changes in serum lipoprotein pattern induced by acute infection. Metabolism 37:859-865.
VADAS, P. 1984. Elevated plasma phospholipase A2 levels: Correlation with the hemodynamic and pulmonary changes in gram-negative septic shock. J. Lab. Clin. Med. 104:873-881.
VADAS, P., J. KEYSTONE, E. STEFANSKI, K. SCOTT, and W. PRUZANSKI. 1992. Induction of circulating group II phospholipase A2 expression in adults with malaria. Infect. Immun. 60:3928-3931.
RINTALA, E. M., and T. J. NEVALAINEN. 1993. Group II phospholipase A2 in sera of febrile patients with microbiologically or clinically documented infections. Clin. Infect. Diseases 17:864-870.
VAN DEN BOSCH, H. 1980. Intracellular phospholipases A. Biochim. Biophys. Acta 604:191-246.
WAITE, M. 1987. The phospholipases: Handbook of lipid research. D. J. Hanahan (Ed.), Vol. 5, Plenum, New York.
ELSBACH, P., and J. WEISS. 1993. Bactericidal/ permeability increasing protein and host defense against Gram-negative bacteria and endotoxin. Curr. Opin. Immunol. 5:103-107.
GROEN, J., B. K. TJIONG, and C. E. KAMMINGA. 1952. The influence of nutrition, individuality and some other factors, including various forms of stress, on the serum cholesterol: An experiment of nine months duration in 60 normal human volunteers. Voeding 13:556-587.
ECKEY, R., M. MENSCHIKOWSKI, P. LATTKE, and W. JAROSS. 1997. Minimal oxidation and storage of low density lipoproteins result in an increased susceptibility to phospholipid hydrolysis by phospholipase A2. Atherosclerosis 132:165-176.
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Menschikowski, M., Eckey, R., Pietzsch, J. et al. Expression of Human Secretory Group IIA Phospholipase A2 is Associated with Reduced Concentrations of Plasma Cholesterol in Transgenic Mice. Inflammation 24, 227–237 (2000). https://doi.org/10.1023/A:1007061413234
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DOI: https://doi.org/10.1023/A:1007061413234