Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL

Mikael Larsson; Christopher M. Allan; Rachel S. Jung; Patrick J. Heizer; Anne P. Beigneux; Stephen G. Young; Loren G. Fong

doi:10.1194/jlr.M078220

Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL[S]

Departments of Medicine^* and Human Genetics, University of California Los Angeles, Los Angeles, CA 90095
^† David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095

↵1To whom correspondence should be addressed. e-mail: mlarsson{at}mednet.ucla.edu (M.L.); sgyoung{at}mednet.ucla.edu (S.G.Y.); lfong{at}mednet.ucla.edu (L.G.F.)

Abstract

ApoC-III is often assumed to retard the intravascular processing of triglyceride-rich lipoproteins (TRLs) by inhibiting LPL, but that view is based largely on studies of free LPL. We now recognize that intravascular LPL is neither free nor loosely bound, but instead is tightly bound to glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) on endothelial cells. Here, we revisited the effects of apoC-III on LPL, focusing on apoC-III’s capacity to affect the activity of GPIHBP1-bound LPL. We found that TRLs from APOC3 transgenic mice bound normally to GPIHBP1-bound LPL on cultured cells in vitro and to heart capillaries in vivo. However, the triglycerides in apoC-III–enriched TRLs were hydrolyzed more slowly by free LPL, and the inhibitory effect of apoC-III on triglyceride lipolysis was exaggerated when LPL was bound to GPIHBP1 on the surface of agarose beads. Also, recombinant apoC-III reduced triglyceride hydrolysis by free LPL only modestly, but the inhibitory effect was greater when the LPL was bound to GPIHBP1. A mutant apoC-III associated with low plasma triglyceride levels (p.A23T) displayed a reduced capacity to inhibit free and GPIHBP1-bound LPL. Our results show that apoC-III potently inhibits triglyceride hydrolysis when LPL is bound to GPIHBP1.

Footnotes

Abbreviations:

IR

infrared

GPIHBP1

glycosylphosphatidylinositol-anchored HDL-binding protein 1

NP40

nonidet P-40

TRL

triglyceride-rich lipoprotein
This work was supported by Foundation for the National Institutes of Health Grant P01 HL090553, Fondation Leducq Transatlantic Network Grant 12CVD04, American Heart Association Grant 15POST22960055, and the Wenner-Gren Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
↵[S]. The online version of this article (available at http://www.jlr.org) contains a supplement.