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 (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.
authors.affiliation: Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gusarova
authors.affiliation: Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Serena
authors.initials: S
authors.lastname: Banfi
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.affiliation: Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.affiliation: Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001057:Apolipoproteins E / Q000172:deficiency; D002784:Cholesterol / Q000097:blood; D020868:Gene Silencing; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D011817:Rabbits; D011973:Receptors, LDL / Q000172:deficiency; D053668:Syndecan-1 / Q000172:deficiency; D014280:Triglycerides / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D053668:Syndecan-1; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; D002784:Cholesterol
keywords: angiopoietin-like protein 3; cholesterol; dyslipidemias; lipase/endothelial; lipase/lipoprotein; very low density lipoprotein