A Pressure-dependent Model for the Regulation of Lipoprotein Lipase by Apolipoprotein C-II

Nathan L Meyers,Mikael Larsson,Gunilla Olivecrona,Donald M Small

doi:10.1074/jbc.m114.629865

Nathan L Meyers, Mikael Larsson + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m114.629865

Copy DOI

Abstract

Apolipoprotein C-II (apoC-II) is the co-factor for lipoprotein lipase (LPL) at the surface of triacylglycerol-rich lipoproteins. LPL hydrolyzes triacylglycerol, which increases local surface pressure as surface area decreases and amphipathic products transiently accumulate at the lipoprotein surface. To understand how apoC-II adapts to these pressure changes, we characterized the behavior of apoC-II at multiple lipid/water interfaces. ApoC-II adsorption to a triacylglycerol/water interface resulted in large increases in surface pressure. ApoC-II was exchangeable at this interface and desorbed on interfacial compressions. These compressions increase surface pressure and mimic the action of LPL. Analysis of gradual compressions showed that apoC-II undergoes a two-step desorption, which indicates that lipid-bound apoC-II can exhibit at least two conformations. We characterized apoC-II at phospholipid/triacylglycerol/water interfaces, which more closely mimic lipoprotein surfaces. ApoC-II had a large exclusion pressure, similar to that of apoC-I and apoC-III. However, apoC-II desorbed at retention pressures higher than those seen with the other apoCs. This suggests that it is unlikely that apoC-I and apoC-III inhibit LPL via displacement of apoC-II from the lipoprotein surface. Upon rapid compressions and re-expansions, re-adsorption of apoC-II increased pressure by lower amounts than its initial adsorption. This indicates that apoC-II removed phospholipid from the interface upon desorption. These results suggest that apoC-II regulates the activity of LPL in a pressure-dependent manner. ApoC-II is provided as a component of triacylglycerol-rich lipoproteins and is the co-factor for LPL as pressure increases. Above its retention pressure, apoC-II desorbs and removes phospholipid. This triggers release of LPL from lipoproteins.

Highlights

Apolipoprotein C-II is the cofactor for lipoprotein lipase (LPL), the central enzyme for plasma triglyceride metabolism
ApoC-II Binds to Lipid/Water Interfaces with High Affinity Resulting in Large Surface Pressure Modifications—This study characterized the effects of Apolipoprotein C-II (apoC-II) adsorption on the surface pressure of lipoprotein-like lipid/water interfaces, which reflect the ability of apoC-II to bind and insert into the interfaces
Because surface pressure increases significantly at the site of LPL activity on lipoprotein surfaces, we hypothesized that the enzyme’s cofactor apoC-II must have a high affinity for lipids

Summary

Background

Apolipoprotein C-II (apoC-II) is the cofactor for lipoprotein lipase (LPL), the central enzyme for plasma triglyceride metabolism. LPL is active at mixed TG/phospholipid and pure phospholipid monolayers of lower surface pressures but requires apoC-II for activity above a critical pressure [14, 15] These results and others [28] suggest that apoC-II interacts with LPL to induce correct alignment of the complex at the lipoprotein surface and facilitate substrate exposure to the catalytic site at higher pressures. Expansion and compression of these interfaces mimic the pressure changes induced by LPL activity [31, 32] Gradual compression of these interfaces reveals the pressures at which lipid-bound apoC-II molecules undergo conformational rearrangements (30 –32, 37). These conformational rearrangements were probed by study of N- and C-terminal apoC-II fragments

Experimental Procedures

Results

Discussion