Expression of human secretory group IIA phospholipase A(2) is associated with reduced concentrations of plasma cholesterol in transgenic mice

It is well known that acute and chronic inflammatory reactions are accompan ied by markedly decreased concentrations of plasma total cholesterol. Howev er, the mechanisms underlying this hypocholesterolemia are not yet complete ly understood. To explore the question of whether an increased serum activi ty of secretory group IIA phospholipase A(2) (sPLA(2)) may contribute to th e development of hypocholesterolemia during inflammation, the lipids and li poprotein patterns in the plasma of transgenic mice overexpressing the huma n sPLA(2) gene were studied and compared with those of nontransgenic contro ls. The mean plasma enzyme activities determined by using [C-14]-oleate lab eled Escherichia coli-membranes were found to be 331 +/- 262 U/1 in transge nic mice while the catalytic activity in plasma of controls was below the a nalytical sensitivity of the assay (0.5 U/1). Compared to nontransgenic lit termates, sPLA(2)-transgenic mice exhibited significantly lower plasma conc entrations of total cholesterol (2.53 +/- 0.37 mmol/l vs. 3.49 +/- 0.44 mmo l/l, p < 0.0001). The reduction of total cholesterol was due to decreased H DL 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 transg enic mice were selectively depleted in free and esterified cholesterol, whe reas HDL of the two animal groups contained comparable percentages of chole sterol. The triglycerides were significantly enriched in LDL and HDL, but t ended to be less in VLDL of transgenic mice. In conclusion, the results of the study have demonstrated that the expression of sPLA(2) may influence th e metabolism of lipoproteins, possibly contributing to the development of h ypocholesterolemia during inflammation.