Overexpression of Secretory Phospholipase A2 Causes Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein Cholesteryl Ester and Apolipoprotein A-I

Abstract

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. 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. Plasma concentrations of high density lipoprotein (HDL) 1 cholesterol and its major apoprotein apoA-I are inversely associated with atherosclerotic cardiovascular disease (1, 2). The factors responsible for the substantial variation in HDL cholesterol and apoA-I levels in humans remain incompletely understood. Metabolic studies of HDL and apoA-I in humans have established that variation in their levels is due in substantial part to variation in the rate of apoA-I catabolism (3-7). Although the determinants of apoA-I catabolism have not been fully elucidated, the size and lipid composition of HDL have been recognized to substantially influence the catabolic rate of apoA-I (8, 9).One clinical setting that is invariably associated with reduced HDL cholesterol and apoA-I levels is systemic inflammation. Acute inflammatory states such as sepsis are associated with profoundly reduced HDL cholesterol levels (10). Furthermore, chronic inflammatory states such as rheumatoid arthritis and systemic lupus are also associated with reduced levels of HDL cholesterol (11-18), as well as with increased risk of cardiovascular disease (19,20). One of the major factors thought to be implicated in the reduced levels of HDL cholesterol during inflammation is the serum amyloid A (SAA) protein, which increases markedly during acute infection and inflammation and is also elevated in chronic inflammatory states (10,21,22). However, expression of SAA has never been directly demonstrated to alter HDL metabolism in vivo in the absence of systemic inflammation. We recently demonstrated that marked overexpression of human SAA alone in the absence of a generalized acute phase response had no effect on HDL cholesterol and apoA-I levels in human apoA-I transgenic mice (23). This observation raised the question as to whether other factors associated with systemic inflammation may modulate HDL metabolism.Group IIA secretory phospholipase A 2 (sPLA 2 ) is an acute phase protein and plasma leve...

Hypocholesterolemia in Clinically Serious Conditions - Review

“…Decrease in HDL-cholesterol may be related to high concentrations of phospholipase A 2 (ref. 55 ), or to downregulation of the ATP-binding cassette transporter-1 gene 56 . Increased TNF production in patients with septic shock has been shown to correlate with low total cholesterol concentration and concentrations of apolipoproteins A 1 and B (ref.…”

Improvement of lipid profile is accompanied by atheroprotective alterations in high‐density lipoprotein composition upon tumor necrosis factor blockade: A prospective cohort study in ankylosing spondylitis

“…It has been suggested that remodeling of HDL through activation of secretory phospholipase A 2 may be an alternative explanation for reduced HDL-c levels during the acute-phase response. Overexpression of this enzyme in mice leads to decreased HDL-c levels and enhanced HDL-c catabolism (29,(38)(39)(40). In addition, inflammation may convert HDL de novo into a more proatherogenic form by coordinate but inverse transcriptional regulation of SAA and Apo A-I in the liver (30).…”

Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase

“…Plasma decay curves for both tracers were generated by dividing the plasma radioactivity at each time point by the radioactivity at the initial 5-min time point after tracer injection. Fractional catabolic rates (FCRs) were determined from the area under the plasma disappearance curves fitted to a bicompartmental model by use of the SAAM II program (22). The use of 3 H-cholesteryl ether affects neither turnover rates in vivo nor SR-BI-mediated uptake of the label into LdlA[mSR-BI] cells in vitro compared with 3 H cholesteryl ester-labeled HDL (data not shown).…”

“…Plasma total cholesterol, triglycerides, and phospholipids were measured enzymatically using commercially available reagents (Wako Pure Chemical Industries, Neuss, Germany). Pooled plasma samples were subjected to fast protein liquid chromatography gel filtration using a Superose 6 column (GE Healthcare) as described (22). Individual fractions were assayed for cholesterol concentrations as described above.…”

“…For the analysis of HDL composition, HDL was isolated from 100 l of mouse plasma by tabletop sequential ultracentrifugation (1.063 Ͻ d Ͻ 1.21) as described (22), and concentrations of total and free cholesterol, phospholipids, and triglycerides were determined enzymatically as described above. Protein concentrations were measured using the BCA assay (Pierce).…”