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Papers In Press, published online ahead of print May 1, 2007
J. Lipid Res., doi:10.1194/jlr.P600011-JLR200

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Journal of Lipid Research, Vol. 48, 1190-1203, May 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions

Chunyu Zheng^*, Christina Khoo^1,*, Katsunori Ikewaki and Frank M. Sacks^2,*

^* Department of Nutrition, Harvard School of Public Health, Boston, MA 02115
Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan 105-8461

The online version of this article (available at http://www.jlr.org) contains supplementary data.

Published, JLR Papers in Press, February 21, 2007.

¹ Present address of C. Khoo: Hill's Pet Nutrition, Topeka, KS 66617.

² To whom correspondence should be addressed. e-mail: fsacks{at}hsph.harvard.edu

ABSTRACT

The atherogenicity theory for triglyceride-rich lipoproteins (TRLs; VLDL + intermediate density lipoprotein) generally cites the action of apolipoprotein C-III (apoC-III), a component of some TRLs, to retard their metabolism in plasma. We studied the kinetics of multiple TRL and LDL subfractions according to the content of apoC-III and apoE in 11 hypertriglyceridemic and normolipidemic persons. The liver secretes mainly two types of apoB lipoproteins: TRL with apoC-III and LDL without apoC-III. Approximately 45% of TRLs with apoC-III are secreted together with apoE. Contrary to expectation, TRLs with apoC-III but not apoE have fast catabolism, losing some or all of their apoC-III and becoming LDL. In contrast, apoE directs TRL flux toward rapid clearance, limiting LDL formation. Direct clearance of TRL with apoC-III is suppressed among particles also containing apoE. TRLs without apoC-III or apoE are a minor, slow-metabolizing precursor of LDL with little direct removal. Increased VLDL apoC-III levels are correlated with increased VLDL production rather than with slow particle turnover. Finally, hypertriglyceridemic subjects have significantly greater production of apoC-III-containing VLDL and global prolongation in residence time of all particle types. ApoE may be the key determinant of the metabolic fate of atherogenic apoC-III-containing TRLs in plasma, channeling them toward removal from the circulation and reducing the formation of LDLs, both those with apoC-III and the main type without apoC-III.

Supplementary key words kinetics • stable isotopes • apolipoprotein B-100 • apolipoprotein E • low density lipoprotein

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