Key result
Angptl3 ASO enhances reverse cholesterol transport across preclinical models regardless of HDL-C levels.
Why the study?
ANGPTL3 has emerged as a promising therapeutic target for cardiovascular disease, but the effect of ANGPTL3 inhibition on reverse cholesterol transport remained unclear.
Does Angptl3 ASO improve reverse cholesterol transport in hyperlipidemic mouse models?
Does Angptl3 ASO improve reverse cholesterol transport in hyperlipidemic mouse models?
p-value: p=<0.05
Inhibition of ANGPTL3 not only reduces proatherogenic lipids but also enhances HDL-mediated reverse cholesterol transport, supporting its atheroprotective potential.
May support atheroprotective effects of ANGPTL3 inhibition via RCT; hypothesis-generating for human translation.
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.
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Bell et al. (2021) studied Hyperlipidemia. Angptl3 antisense oligonucleotide (ASO) vs. PBS or control ASO (50 mg/kg/wk) was evaluated on Reverse cholesterol transport (macrophage-to-feces in vivo RCT assay) (p=<0.05). Treatment with the Angptl3 ASO enhanced reverse cholesterol transport in all mouse models tested, regardless of the effect on HDL-C levels.
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