Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

Abstract

This article is available online at http://www.jlr.org an enzyme that catalyzes an early step in cholesterol biosynthesis, effectively lower plasma LDL-C levels and prevent CHD ( 2 ). Human genetic studies have provided several new targets for LDL-C lowering. Individuals who lack ApoB ( 3 ), or microsomal transfer protein (MTP), the enzyme that transfers TG to TG-rich lipoproteins in the liver and intestine ( 4 ), have very low LDL levels. Agents that suppress ApoB expression ( 5 ) or inhibit MTP activity ( 6 ) are now available for treatment of severe hypercholesterolemia in individuals with homozygous familial hypercholesterolemia. Loss-of-function mutations in PCSK9, a secreted proprotein convertase that promotes degradation of the LDL receptor (LDLR), cause a 30% reduction in LDL-C and substantial protection from CHD ( 7 ). Anti-PCSK9 antibodies lower circulating LDL-C levels ( 8 ) and clinical trials are now underway to determine whether there is an associated reduction in CHD ( 9 ).More recently, several families with inactivating mutations in angiopoietin-like protein 3 ( ANGPTL3 ) were identifi ed ( 10-12 ). Family members with two loss-of-function mutations in ANGPTL3 have striking pan-hypolipidemia; plasma levels of TGs, NEFAs, VLDL-cholesterol (VLDL-C), LDL-C, and HDL-cholesterol (HDL-C) are all markedly reduced. The mechanisms by which ANGPTL3 modulates TG metabolism have been extensively investigated ( 13 ). ANGPTL3 inhibits the activity of two intravascular lipases: LPL, which catalyzes hydrolysis of TGs in TG-rich lipoproteins, and endothelial lipase (EL), which hydrolyzes lipoprotein phospholipids ( 14-16 ). Thus, increased activity of LPL and EL may account for the low plasma levels of TG 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 ANG-PTL3 defi ciency refl ect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 defi ciency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic defi ciencies in key proteins involved in clearance of ApoBcontaining 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-␤ VLDL 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 fi ndings 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(...

Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia

“…The reductions achieved correlated with baseline lipid levels. Similar results have been reported with evinacumab (REGN-1500), an antibody-based inhibitor of ANGPTL3 [62]. A dose-ranging study of evinacumab in three patients with HoFH showed it could reduce LDL-C by 46% [63].…”

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

“…In fact, the attenuated postprandial lipemia together with reduced flux of FFAs directed to the liver may explain the lower VLDL secretion rate and fasting TG reported in homozygous FHBL2 (13) and recently confirmed during antibody-mediated inhibition of ANGPTL3 (48). Moreover, the faster hepatic removal of remnants may decrease the fraction that is converted in circulation into LDL, thereby lowering LDL production and fasting LDL-C levels.…”

“…*P < 0.001 for comparison between homozygous subjects and controls; † P < 0.001 for comparison between homozygous and heterozygous subjects; and ‡ P < 0.001 for comparison between heterozygous subjects and controls. FFAs (48). More detailed tracer studies are needed to clarify the role of ANGPTL3 in fatty acid metabolism.…”

ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys

“…The mechanism responsible for the LDL-lowering effect of ANGPTL3 is currently not clear, but appears not to involve the major canonical pathways of clearance of ApoB-containing lipoproteins ( 34 ) .…”