Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

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

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 <sup>125</sup>I-βVLDL or mouse <sup>125</sup>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 non-canonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.

Original languageEnglish (US)
Pages (from-to)1296-1307
Number of pages12
JournalJournal of Lipid Research
Volume56
Issue number7
DOIs
StatePublished - Jul 1 2015

Fingerprint

Angiopoietins
Liver
Protein Deficiency
Proteins
Apolipoproteins B
Lipase
Lipoproteins
Animals
Fatty Acids
Apolipoprotein B-100
Apolipoproteins E
LDL Cholesterol
HDL Cholesterol
Plasmas
very low density lipoprotein triglyceride
Cholesterol
Monoclonal Antibodies
Rabbits
Antibodies
Enzymes

Keywords

  • Angiopoietin-like protein 3
  • Cholesterol
  • Dyslipidemias
  • Lipase/endothelial
  • Lipase/lipoprotein
  • Very low density lipoprotein

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. / Wang, Yan; Gusarova, Viktoria; Banfi, Serena; Gromada, Jesper; Cohen, Jonathan C.; Hobbs, Helen H.

In: Journal of Lipid Research, Vol. 56, No. 7, 01.07.2015, p. 1296-1307.

Research output: Contribution to journalArticle

Wang, Yan ; Gusarova, Viktoria ; Banfi, Serena ; Gromada, Jesper ; Cohen, Jonathan C. ; Hobbs, Helen H. / Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. In: Journal of Lipid Research. 2015 ; Vol. 56, No. 7. pp. 1296-1307.
@article{0e1cb500210e49ebba514b2be2891ba6,
title = "Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion",
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 125I-βVLDL or mouse 125I-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 non-canonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.",
keywords = "Angiopoietin-like protein 3, Cholesterol, Dyslipidemias, Lipase/endothelial, Lipase/lipoprotein, Very low density lipoprotein",
author = "Yan Wang and Viktoria Gusarova and Serena Banfi and Jesper Gromada and Cohen, {Jonathan C.} and Hobbs, {Helen H.}",
year = "2015",
month = "7",
day = "1",
doi = "10.1194/jlr.M054882",
language = "English (US)",
volume = "56",
pages = "1296--1307",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "7",

}

TY - JOUR

T1 - Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

AU - Wang, Yan

AU - Gusarova, Viktoria

AU - Banfi, Serena

AU - Gromada, Jesper

AU - Cohen, Jonathan C.

AU - Hobbs, Helen H.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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 125I-βVLDL or mouse 125I-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 non-canonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.

AB - 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 125I-βVLDL or mouse 125I-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 non-canonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.

KW - Angiopoietin-like protein 3

KW - Cholesterol

KW - Dyslipidemias

KW - Lipase/endothelial

KW - Lipase/lipoprotein

KW - Very low density lipoprotein

UR - http://www.scopus.com/inward/record.url?scp=84937157286&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937157286&partnerID=8YFLogxK

U2 - 10.1194/jlr.M054882

DO - 10.1194/jlr.M054882

M3 - Article

C2 - 25954050

AN - SCOPUS:84937157286

VL - 56

SP - 1296

EP - 1307

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 7

ER -