Antisense oligonucleotide–mediated inhibition of angiopoietin-like protein 3 increases reverse cholesterol transport in mice

Thomas A Bell,Mingxia Liu,Aaron J Donner,Richard G Lee,Adam E Mullick,Rosanne M Crooke

doi:10.1016/j.jlr.2021.100101

Thomas A Bell, Mingxia Liu + Show 4 more

Open Access

https://doi.org/10.1016/j.jlr.2021.100101

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Abstract

Supported by an abundance of experimental and genetic evidence, angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for cardiovascular disease. ANGPTL3 is primarily produced by the liver and is a potent modulator of plasma lipids and lipoproteins. Experimental models and subjects with loss-of-function Angptl3 mutations typically present with lower levels of HDL-C than noncarriers. The effect of ANGPTL3 on HDL-C is typically attributed to its function as an inhibitor of the enzyme endothelial lipase. The ability to facilitate reverse cholesterol transport (RCT), the transport of cholesterol from peripheral tissues back to the liver, is a proposed antiatherogenic property of HDL. However, the effect of ANGPTL3 inhibition on RCT remains unclear. Here, we performed a series of dose-response and RCT studies using an Angptl3 antisense oligonucleotide (ASO) in mouse models with varying plasma lipid profiles ranging from moderately to severely hyperlipidemic. Angptl3 ASO-mediated reduction in HDL-C was limited to the model with moderate lipidemia, where the majority of plasma cholesterol was associated with HDL. Surprisingly, regardless of the effect on HDL-C, treatment with the Angptl3 ASO enhanced RCT in all models tested. The observations from the RCT assays were confirmed in HDL clearance studies, where mice treated with the Angptl3 ASO displayed increased plasma clearance and hepatic uptake of labeled HDL. The results from our studies suggest that inhibition of ANGPTL3 not only reduces levels of proatherogenic lipids but also improves HDL-mediated RCT.

Highlights

Supported by an abundance of experimental and genetic evidence, angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for cardiovascular disease
To determine the effect of ANGPTL3 inhibition on HDL-C and reverse cholesterol transport (RCT), we performed a series of dose-response and RCT experiments with an antisense oligonucleotide (ASO) targeting Angptl3 in mouse models with dramatically different lipoprotein profiles, ranging from mildly to severely hyperlipidemic
Given the lifelong reductions in proatherogenic LDL-C commonly found in subjects with familial combined hypobetalipoproteinemia (FHBL2), it is highly unlikely that lower levels of HDL-C would significantly contribute to atherosclerotic cardiovascular disease (ASCVD) progression in this patient population

Summary

Introduction

Supported by an abundance of experimental and genetic evidence, angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for cardiovascular disease. The dramatic increase in hypertriglyceridemia associated with diabetes, obesity, and other metabolic disorders threatens to put more patients at risk for ASCVD [4] This has prompted the development of a new generation of therapeutics for cardiovascular disease that can lower plasma TG as well as reduce broader non–HDL-C pools in addition to LDL-C. Additional studies performed in the KK mice with the Angptl LOF mutation found ANGPTL3 protein deficiency was associated with lower levels of HDL-C and HDLphospholipid [8] This effect on HDL was attributed to ANGPTL3 being an inhibitor of EL as well as LpL activity. Additional studies evaluating HDL clearance confirmed that inhibition of ANGPTL3 improved RCT These results suggest that inhibition of ANGPTL3 can reduce levels of proatherogenic lipoproteins and enhance a potentially protective function of HDL, irrespective of the effect on HDL-C

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