title: Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice.
abstract: 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.
authors.affiliation: TNO-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Jong
authors.forename: P C
authors.initials: PC
authors.lastname: Rensen
authors.forename: V E
authors.initials: VE
authors.lastname: Dahlmans
authors.forename: H
authors.initials: H
authors.lastname: van der Boom
authors.forename: T J
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: L M
authors.initials: LM
authors.lastname: Havekes
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000172:deficiency* / Q000235:genetics; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002914:Chylomicrons / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D017353:Gene Deletion; D006868:Hydrolysis; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D002914:Chylomicrons; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D008071:Lipoprotein Lipase