Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice
Gaubius Instituut TNO
van der Boom, H.
van Berkel, T.J.C.
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. Chemicals/CAS: Apolipoprotein C-III; Apolipoproteins C; Apolipoproteins E; Chylomicrons; Lipoprotein Lipase, EC 22.214.171.124; Lipoproteins, VLDL; Triglycerides
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Mice, Inbred C57BL
Journal of Lipid Research, 42 (42), 1578-1585