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1 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine and NWFZ, Humboldt University, Berlin, Germany
2 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3 Department of Biology, University of Delaware, Newark, DE, USA
* To whom correspondence should be addressed. E-mail: rader{at}mail.med.upenn.edu.
The acute phase protein secretory phospholipase A2 (sPLA2) influences the metabolism of high density lipoproteins (HDL). The adrenals are known to utilize HDL cholesterol as a source of sterols. The aim of the present study was to test the hypothesis that sPLA2 enhances the selective uptake of HDL into the adrenals in response to acute inflammation as a possible physiologic role for the sPLA2 HDL interaction. Human sPLA2 transgenic mice , in which sPLA2 expression is upregulated by inflammatory stimuli, were used. 10 h after induction of the acute phase response (APR) by injection of bacterial lipopolysaccharide (LPS), plasma levels of HDL cholesterol decreased significantly in sPLA2 transgenic mice (-18%, p<0.05), but remained unchanged in wildtype mice. The fractional catabolic rates of both 125I-tyramine-cellobiose(TC)-HDL and 3H-cholesteryl ether increased significantly in the sPLA2 transgenic mice after induction of the APR (0.18 ± 0.01 vs. 0.21 ± 0.01 pool/h, p<0.05. 0.31 ± 0.02 vs. 0.42 ± 0.05 pool/h, p<0.05, resp.), but remained unchanged in the wildtype mice (0.10 ± 0.01 pool/h. 0.22 ± 0.02 pool/h, resp.). After induction of the APR in both groups HDL holoparticle uptake by the liver was increased (p<0.001). sPLA2 transgenic mice had 2.4-fold higher selective uptake into the adrenals after induction of the APR than wildtype mice (156 ± 6 vs. 65 ± 5 %/µg tissue protein, p<0.001). In summary, upregulation of sPLA2 expression during the APR specifically increases the selective uptake of HDL cholesteryl ester into the adrenals. These data suggest a novel metabolic role for sPLA2: modification of HDL during the APR to promote increased adrenal uptake of HDL cholesteryl ester to serve as source for steroid hormone synthesis.
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