Abstract
BackgroundPrevious studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes. Since apoproteins are now known to have important roles in host defense, we have separated these subclasses according to their apoprotein content and characterized their changes during experimental endotoxemia in human volunteers.MethodsWe have studied apoB- and apoA containing lipoprotein subclasses in twelve healthy male volunteers before and for 8 h after a single dose of endotoxin (ET; 2 μg/kg) to stimulate inflammation.ResultsAfter endotoxin, TG, TC, apoB and the apoB-containing lipoprotein cholesterol-rich subclass LpB and two of the three triglyceride-rich subclasses (TGRLP: Lp:B:C, LpB:C:E+ LpB:E) all declined. In contrast, the third TGRLP, LpA-II:B:C:D:E (“complex particle”), after reaching a nadir at 4 h rose 49% above baseline, p = .006 at 8 h and became the dominant particle in the TGRLP pool. This increment exceeds the threshold of > 25% change required for designation as an acute phase protein. Simultaneous decreases in LpA-I:A-II and LpB:C:E + LpB:E suggest that these subclasses undergo post-translational modification and contribute to the formation of new LpA-II:B:C:D:E particles.ConclusionsWe have identified a new acute phase lipoprotein whose apoprotein constituents have metabolic and immunoregulatory properties applicable to host defense that make it well constituted to engage in the APR.
Highlights
Previous studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes
To determine the distribution of apoC-III and apoE between the apoB- and apoA- lipoproteins following endotoxin or saline treatment, the binding of each was measured by electroimmunoassay in heparin soluble (HS; apoA) and heparin precipitate (HP; apoB) fractions and changes in their apoE content expressed as apoE-HS (HDL)/HP (VLDL+ Low density lioprotein (LDL)) ratios
While the plasma TG declined from baseline and the triglyceride-rich lipoproteins (TGRLP) pool size contracted in the ET group, the number of Lp-AII:B:C:D:E particles relative to LpB:C and LpB:C:E + LpB:E increased and LpA-II: B:C:D:E (LpA-II):B:C:D:E: became the predominant TGRLP subclass at 6 h and 8 h (p = .001; Fig. 2f )
Summary
Previous studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes. The acute phase reaction (APR) is an integral component of host defense that contributes to the initiation, activation, and propagation of events that are integral features of innate immunity [1] This highly conserved transcriptional response is driven by inflammatory cytokines released from mononuclear cells that activate expression of multiple genes [2] that alter the hepatic secretion of a number of plasma proteins and lipoproteins that have pathophysiological actions [3]. One of these many changes is a rise in triglyceride-rich lipoproteins (TGRLP) that frequently is observed during sepsis. Density fractions are very heterogeneous and contain several discrete subclasses that differ in their apoprotein and lipid composition, function, density, and metabolism and are not detected when conventional density fraction fractions are measured [9]
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