Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

Wang, Yan; Gusarova, Viktoria; Banfi, Serena; Gromada, Jesper; Cohen, Jonathan C.; Hobbs, Helen H.

doi:10.1194/jlr.m054882

Cited by 189Lipid metabolism and disordersCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

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Wang, Yan, Gusarova, Viktoria, Banfi, Serena, Gromada, Jesper, Cohen, Jonathan C., Hobbs, Helen H.·2015·Journal of Lipid Research

DOI 10.1194/jlr.m054882PMC PMC4479334

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Abstract

Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies in key proteins involved in clearance of ApoB-containing lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe, Ldlr, Lrp1, and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit (125)I-βVLDL or mouse (125)I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our findings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.

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In dose-finding studies, evinacumab reduced TG and LDL-C by up to 75% and 23%, respectively; the latter effect appears independent of the LDL receptor pathway.
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Authors: Wang, Y., Gusarova, V., Banfi, S., Gromada, J., Cohen, J. C., & Hobbs, H. H.
Affiliations: Howard Hughes Medical Institute (US)
Regeneron (United States) (US)
The University of Texas Southwestern Medical Center (US)
ORCID: Wang, Yan
Gusarova, Viktoria
Gromada, Jesper
Cohen, Jonathan C.
Hobbs, Helen H.
Venue: Journal of Lipid Research
Publisher: Elsevier BV
Published: 2015-07
Volume: 56
Issue: 7
Pages: 1296-1307
ISSN: 0022-2275 (ISSN-L)
DOI: 10.1194/jlr.m054882
PMC: PMC4479334
OpenAlex: W2165200875
Cited by: 189
References: 61
Citations by year: 2026: 11 · 2025: 9 · 2024: 13 · 2023: 18 · 2022: 16 · 2021: 27 · 2020: 30 · 2019: 16 · 2018: 11 · 2017: 18 · 2016: 16 · 2015: 3
FWCI: 11.65
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 1906 d)
Locations: Journal of Lipid Research (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (UL1TR001105)
National Heart, Lung, and Blood Institute (P01 HL-20948, P01HL020948)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090066)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords: ANGPTL3, VLDL triglyceride secretion, hepatic lipoprotein secretion, apoB-containing lipoproteins, lipoprotein clearance, LDL cholesterol, lipoprotein lipase, endothelial lipase, apolipoprotein E, LDL receptor, LRP1, syndecan-1, hypolipidemia
MeSH terms: Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Animals, Antibodies, Monoclonal, Apolipoproteins E, Cholesterol, Humans, Lipoproteins, VLDL, Liver, Male, Rabbits, Receptors, LDL, Triglycerides, Gene Silencing, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Angiopoietins, Mice, Syndecan-1

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Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

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