Overexpression of secretory phospholipase A(2) causes rapid catabolism and altered tissue uptake of high density lipoprotein cholesteryl ester and apolipoprotein A-I

Plasma levels of high density lipoprotein (HDL) cholesterol and its major protein component apolipoprotein (apo) A-I are significantly reduced in both acute and chronic inflammatory conditions, but the basis for this phenomenon is not well understood. We hypothesized that secretory phospholipase A(2) (sPLA(2)), an acute phase protein that has been found in association with HDL, promotes HDL catabolism. A series of HDL metabolic studies were performed in transgenic mice that specifically overexpress human sPLA(2) but have no evidence of local or systemic inflammation. We found that HDL isolated from these mice have a significantly lower phospholipid and cholesteryl ester and significantly greater triglyceride content. The fractional catabolic rate (FCR) of (125)I-HDL was significantly faster in sPLA(2) transgenic mice (4.08 +/- 0.01 pools/day) compared with control wild-type littermates (2.16 +/- 0.48 pools/day). (125)I-HDL isolated from sPLA(2) transgenic mice was catabolized significantly faster than (131)I-HDL isolated from wild-type mice after injection in wild-type mice (p < 0.001). Injection of (125)I-tyramine-cellobiose-HDL demonstrated significantly greater degradation of HDL apolipoproteins in the kidneys of sPLA(2) transgenic mice compared with control mice (p < 0.05). The fractional catabolic rate of (3)H]cholesteryl ether HDL was significantly faster in sPLA(2)-overexpressing mice (6.48 +/- 0.24 pools/day) compared with controls (4.80 +/- 0.72 pools/day). Uptake of (3)H] cholesteryl ether into the livers and adrenals of sPLA(2) transgenic mice was significantly enhanced compared with control mice. In summary, these data demonstrate that overexpression of sPLA(2) alone in the absence of inflammation causes profound alterations of HDL metabolism in vivo and are consistent with the hypothesis that sPLA(2) may promote HDL catabolism in acute and chronic inflammatory conditions.