Effects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism

Reyes-Soffer, Gissette; Sztalryd, Carol; Horenstein, Richard B.; Holleran, Stephen; Matveyenko, Anastasiya; Thomas, Tiffany; Nandakumar, Renu; Ngai, Colleen; Karmally, Wahida; Ginsberg, Henry N.; Ramakrishnan, Rajasekhar; Pollin, Toni I.

doi:10.1161/atvbaha.118.311476

Cited by 97Lipid metabolism and disordersLipoproteins and Cardiovascular HealthLipid metabolism and biosynthesis

Effects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism

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Reyes-Soffer, Gissette, Sztalryd, Carol, Horenstein, Richard B., Holleran, Stephen, Matveyenko, Anastasiya, Thomas, Tiffany, Nandakumar, Renu, Ngai, Colleen +4 more·2019·Arteriosclerosis, Thrombosis, and Vascular Biology

DOI 10.1161/atvbaha.118.311476PMC PMC6309928

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Abstract

Objective—: Apo (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.

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Individuals with LOF APOC3 variants have low plasma TG levels and markedly increased in vivo fractional turnover of VLDL-TG with efficient conversion of VLDL apoB to LDL, indicating increased lipolysis.
“Individuals with LOF APOC3 variants have low plasma TG levels59,60,187 and markedly increased in vivo fractional turnover of VLDL–TG with efficient conversion of VLDL apoB to LDL, indicating increased lipolysis.59,187”
From Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society (2021) · cites this paper as [187]

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Authors: Reyes-Soffer, G., Sztalryd, C., Horenstein, R. B., Holleran, S., Matveyenko, A., Thomas, T., Nandakumar, R., Ngai, C., Karmally, W., Ginsberg, H. N., Ramakrishnan, R., & Pollin, T. I.
Affiliations: From the Columbia University Vagelos College of Physicians and Surgeons, New York (G.R.-S., S.H., A.M., T.T., R.N., C.N., W.K., H.N.G., R.R.)
Maryland School of Medicine, University of Maryland, Baltimore (C.S., R.B.H., T.I.P.)
University of Maryland, Baltimore (US)
Columbia University (US)
ORCID: Holleran, Stephen
Nandakumar, Renu
Karmally, Wahida
Ginsberg, Henry N.
Ramakrishnan, Rajasekhar
Pollin, Toni I.
Venue: Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2019-01
Volume: 39
Issue: 1
Pages: 63-72
ISSN: 1079-5642 (ISSN-L)
1524-4636
DOI: 10.1161/atvbaha.118.311476
PMC: PMC6309928
OpenAlex: W2899689685
Cited by: 97
References: 65
Citations by year: 2026: 7 · 2025: 16 · 2024: 9 · 2023: 10 · 2022: 17 · 2021: 16 · 2020: 14 · 2019: 8
FWCI: 7.18
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Columbia Academic Commons (Columbia University)
Funders: U.S. Department of Veterans Affairs
National Institutes of Health (KL2TR000081, UL1TR001873, KL2TR001874)
National Heart, Lung, and Blood Institute (R35HL135833, R01HL104193)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK072488)
NIH Clinical Center
National Center for Advancing Translational Sciences
Mid-Atlantic Nutrition Obesity Research Center, School of Medicine, University of Maryland (P30 DK072488)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: apolipoprotein C-III, heterozygous deficiency, lipoprotein lipase, apolipoprotein B-100, apolipoprotein C-II, fractional clearance rate, plasma triglycerides
MeSH terms: Adult, Aged, Female, Humans, Lipids, Lipolysis, Lipoproteins, Lipoproteins, VLDL, Male, Middle Aged, Mutation, Apolipoprotein B-100, Apolipoprotein C-III, Lipoproteins, IDL

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Effects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism

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