Abstract
Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes. ApoC-III elevates TG in part by inhibiting LPL. ApoC-III likely inhibits LPL by competing for lipid binding. To probe this, we used oil-drop tensiometry to characterize binding of six apoC-III variants to lipid/water interfaces. This technique monitors the dependence of lipid binding on surface pressure, which increases during TG hydrolysis by LPL. ApoC-III adsorption increased surface pressure by upward of 18 mN/m at phospholipid/TG/water interfaces. ApoC-III was retained to high pressures at these interfaces, desorbing at 21–25 mN/m. Point mutants, which substituted alanine for aromatic residues, impaired the lipid binding of apoC-III. Adsorption and retention pressures decreased by 1–6 mN/m in point mutants, with the magnitude determined by the location of alanine substitutions. Trp42 was most critical to mediating lipid binding. These results strongly correlate with our previous results, linking apoC-III point mutants to increased LPL binding and activity at lipid surfaces. We propose that aromatic residues in the C-terminal half of apoC-III mediate binding to TG-rich lipoproteins. Increased apoC-III expression in the hypertriglyceridemic state allows apoC-III to accumulate on lipoproteins and inhibit LPL by preventing binding and/or access to substrate.
Highlights
Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes
This suggests that the 6× His-tag alters the lipid binding of apoC-III
Because all apoC-III constructs used in this study contain this tag, any differences in lipid binding are due to the point mutations
Summary
Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes. We used oil-drop tensiometry to characterize binding of six apoC-III variants to lipid/water interfaces This technique monitors the dependence of lipid binding on surface pressure, which increases during TG hydrolysis by LPL. Trp was most critical to mediating lipid binding These results strongly correlate with our previous results, linking apoC-III point mutants to increased LPL binding and activity at lipid surfaces. Targeted disruption of apoC-III in mice was associated with the rapid catabolism of TG-rich lipoproteins and a 70% decrease in fasting TG levels [10]. Beyond these mouse models, clinical studies established the importance of apoC-III as a predictor of CVD outcomes. Subjects with loss-of-function mutations in the apoC-III gene exhibited reduced TG and apoC-III levels [17,18,19,20,21], which had a cardioprotective effect
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