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Journal of Lipid Research, Vol. 42, 1578-1585, October 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice

Correspondence to: Louis M. Havekes, at TNO-Prevention and Health, Gaubius Laboratory, Zernikedreef 9, P.O. Box 2215, 2301 CE Leiden, The Netherlands., lm.havekes{at}PG.TNO.NL (E-mail)

Previous studies with hypertriglyceridemic APOC3 transgenic mice have suggested that apolipoprotein C-III (apoC-III) may inhibit either the apoE-mediated hepatic uptake of TG-rich lipoproteins and/or the lipoprotein lipase (LPL)-mediated hydrolysis of TG. Accordingly, apoC3 knockout (apoC3^-/-) mice are hypotriglyceridemic. In the present study, we attempted to elucidate the mechanism(s) underlying these phenomena by intercrossing apoC3^-/- mice with apoE^-/- mice to study the effects of apoC-III deficiency against a hyperlipidemic background. Similar to apoE^+/+ apoC3^-/- mice, apoE^-/-apoC3^-/- mice exhibited a marked reduction in VLDL cholesterol and TG, indicating that the mechanism(s) by which apoC-III deficiency exerts its lipid-lowering effect act independent of apoE. On both backgrounds, apoC3^-/- mice showed normal intestinal lipid absorption and hepatic VLDL TG secretion. However, turnover studies showed that TG-labeled emulsion particles were cleared much more rapidly in apoC3^-/- mice, whereas the clearance of VLDL apoB, as a marker for whole particle uptake by the liver, was not affected. Furthermore, it was shown that cholesteryl oleate-labeled particles were also cleared faster in apoC3^-/- mice. Thus the mechanisms underlying the hypolipidemia in apoC3^-/- mice involve both a more efficient hydrolysis of VLDL TG as well as an enhanced selective clearance of VLDL cholesteryl esters from plasma.

In summary, our studies of apoC3^-/- mice support the concept that apoC-III is an effective inhibitor of VLDL TG hydrolysis and reveal a potential regulating role for apoC-III with respect to the selective uptake of cholesteryl esters. — Jong, M. C., P. C. N. Rensen, V. E. H. Dahlmans, H. van der Boom, T. J. C. van Berkel, and L. M. Havekes. Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice. J. Lipid Res. 2001. 42: 1578–1585.

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