Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition

作者：Meyers Nathan L; Larsson Mikael; Vorrsjo Evelina; Olivecrona Gunilla; Small Donald M^*

来源：The Journal of Lipid Research, 2017, 58(5): 840-852.

DOI：10.1194/jlr.M071126

• lipoprotein lipase
• lipid and lipoprotein metabolism
• LDL/metabolism
• lipid/emulsions
• protein-lipid interaction
• surface pressure
• drop tensiometry

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.(jlr) 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 sub-strate.

• 出版日期2017-5