Overexpression of secretory phospholipase A₂ 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 A₂ (sPLA₂), 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 sPLA₂ 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 ¹²⁵I-HDL was significantly faster in sPLA₂ transgenic mice (4.08 ± 0.01 pools/day) compared with control wild- type littermates (2.16 ± 0.48 pools/day). ¹²⁵I-HDL isolated from sPLA₂ transgenic mice was catabolized significantly faster than ¹³¹I-HDL isolated from wild-type mice after injection in wild-type mice (p < 0.001). Injection of ¹²⁵I-tyramine-cellobiose-HDL demonstrated significantly greater degradation of HDL apolipoproteins in the kidneys of sPLA₂ transgenic mice compared with control mice (p < 0.05). The fractional catabolic rate of [³H]cholesteryl ether HDL was significantly faster in sPLA₂-overexpressing mice (6.48 ± 0.24 pools/day) compared with controls (4.80 ± 0.72 pools/day). Uptake of [³H] cholesteryl ether into the livers and adrenals of sPLA₂ transgenic mice was significantly enhanced compared with control mice. In summary, these data demonstrate that overexpression of sPLA₂ alone in the absence of inflammation causes profound alterations of HDL metabolism in vivo and are consistent with the hypothesis that sPLA₂ may promote HDL catabolism in acute and chronic inflammatory conditions.