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

Previous studies with hypertriglyceridemic APOC3 transgenic mice have sugge sted that apolipoprotein GM (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 a re hypotriglyceridemic. In the present study, we attempted to elucidate the mechanism(s) underlying these phenomena by intercrossing apoC3(-/-) mice w ith apoE(-/-) mice to study the effects of apoC-III deficiency against a hy perlipidemic background. Similar to apoE(+/+) apoC3(-/-) mice, apoE(-/-) mi ce exhibited a marked reduction in VLDL cholesterol and TG, indicating that the mechanism(s) by which apoC-III deficiency exerts its lipid-lowering ef fect act independent of apoE. On both backgrounds, apoC3(-/-) mice showed n ormal intestinal lipid absorption and hepatic VLDL TG secretion. However, t urnover 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. Furthermor e, it was shown that cholesteryl oleate-labeled particles were also cleared faster in apoC3(-/-) mice. Thus the mechanisms underlying the hypolipidemi a in apoC3(-/-) mice involve both a more efficient hydrolysis of VLDL TG as well as an enhanced selective clearance of VLDL cholesteryl esters from pl asma.jlr In summary, our studies of apoC3(-/-) mice support the concept tha t apoC-III is an effective inhibitor of VLDL TG hydrolysis and reveal a pot ential regulating role for apoC-III with respect to the selective uptake of cholesteryl esters.