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dc.contributor.authorReyes-Soffer, G.
dc.contributor.authorSztalryd, C.
dc.contributor.authorHorenstein, R.B.
dc.date.accessioned2019-09-13T14:49:33Z
dc.date.available2019-09-13T14:49:33Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85059246770&doi=10.1161%2fATVBAHA.118.311476&partnerID=40&md5=425f08d713ab3cb2cec78ed3fabfc9c7
dc.identifier.urihttp://hdl.handle.net/10713/10615
dc.description.abstractApo (apolipoprotein) CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of VLDL (very-low-density lipoprotein) triglyceride (TG) and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are heterozygous for the APOC3 R19X null mutation provided the opportunity to determine the effects of a naturally occurring reduction in apo CIII levels on the metabolism of atherogenic containing lipoproteins. Approach and Results - We conducted stable isotope studies of VLDL-TG and apoB100 in 5 individuals heterozygous for the null mutation APOC3 R19X (CT) and their unaffected (CC) siblings. Fractional clearance rates and production rates of VLDL-TG and apoB100 in VLDL, IDL (intermediate-density lipoprotein), LDL, apo CIII, and apo CII were determined. Affected (CT) individuals had 49% reduction in plasma apo CIII levels compared with CCs (P<0.01) and reduced plasma levels of TG (35%, P<0.02), VLDL-TG (45%, P<0.02), and VLDL-apoB100 (36%, P<0.05). These changes were because of higher fractional clearance rates of VLDL-TG and VLDL-apoB100 with no differences in production rates. CTs had higher rates of the conversion of VLDL remnants to LDL compared with CCs. In contrast, rates of direct removal of VLDL remnants did not differ between the groups. As a result, the flux of apoB100 from VLDL to LDL was not reduced, and the plasma levels of LDL-cholesterol and LDL-apoB100 were not lower in the CT group. Apo CIII production rate was lower in CTs compared with CCs, whereas apo CII production rate was not different between the 2 groups. The fractional clearance rates of both apo CIII and apo CII were higher in CTs than CCs. Conclusions - These studies demonstrate that 50% reductions in plasma apo CIII, in otherwise healthy subjects, results in a significantly higher rate of conversion of VLDL to LDL, with little effect on direct hepatic uptake of VLDL. When put in the context of studies demonstrating significant protection from cardiovascular events in individuals with loss of function variants in the APOC3 gene, our results provide strong evidence that therapies which increase the efficiency of conversion of VLDL to LDL, thereby reducing remnant concentrations, should reduce the risk of cardiovascular disease. Copyright 2018 American Heart Association, Inc.en_US
dc.description.sponsorshipThis study was funded by the National Institutes of Health: R01-HL104193 (Pollin), R35 HL135833 (Ginsberg), and KL2TR001874 (Reyes-Soffer).en_US
dc.description.urihttps://doi.org/10.1161/ATVBAHA.118.311476en_US
dc.language.isoen-USen_US
dc.publisherLippincott Williams and Wilkinsen_US
dc.relation.ispartofArteriosclerosis, Thrombosis, and Vascular Biology
dc.subjectapolipoprotein C-IIIen_US
dc.subjectcardiovascular diseasesen_US
dc.subjectisotopesen_US
dc.subjectlipolysisen_US
dc.subjectlipoprotein lipaseen_US
dc.titleEffects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolismen_US
dc.typeArticleen_US
dc.identifier.doi10.1161/ATVBAHA.118.311476
dc.identifier.pmid30580564


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