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

Plasma levels of high density lipoprotein (HDL) cholesterol and its major p rotein component apolipoprotein (apo) A-I are significantly reduced in both acute and chronic inflammatory conditions, but the basis for this phenomen on is not well. understood, We hypothesized that secretory phospholipase A( 2) (sPLA(2)), an acute phase protein that has been found in association wit h HDL, promotes HDL catabolism. A series of HDL metabolic studies were perf ormed in transgenic mice that specifically overexpress human sPLA(2) but ha ve no evidence of local or systemic inflammation, We found that HDL isolate d from these mice have a significantly lower phospholipid and cholesteryl e ster and significantly greater triglyceride content. The fractional catabol ic rate (FCR) of I-125-HDL was significantly faster in sPLA(2) transgenic m ice (4.08 +/- 0.01 pools/day) compared with control wildtype littermates (2 .16 +/- 0.48 pools/day). I-125-HDL isolated from sPLA(2) transgenic mice wa s catabolized significantly faster than I-131-HDL isolated from wild-type m ice after injection in wild-type mice (p < 0.001), Injection of I-125-tyram ine-cellobiose-HDL demonstrated significantly greater degradation of HDL ap olipoproteins in the kidneys of sPLA(2) transgenic mice compared with contr ol mice (p < 0.05), The fractional catabolic rate of [H-3]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 [H- 3] cholesteryl ether into the livers and adrenals of sPLA(2) transgenic mic e was significantly enhanced compared with control mice. In summary, these data demonstrate that overexpression of sPLA(2) alone in the absence of inf lammation causes profound alterations of HDL metabolism in vivo and are con sistent with the hypothesis that sPLA(2) may promote HDL catabolism in acut e and chronic inflammatory conditions.