Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance

Abstract

<jats:p>Angiopoietin-like protein 3 (ANGPTL3) regulates plasma lipids by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-cholesterol (LDL-C) independently of the classical LDL-receptor (LDLR)-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.</jats:p>

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia

“…Recent evidence has confirmed the prominent role that inhibitors of ANGPTL3 have in the removal of triglycerides-rich particles, LDL-C and apo B levels, probably due to an increased clearance of apo B containing lipoproteins and their remnants [ 33 ]. Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, and 4 are potentially an efficient therapeutic strategy for cardiovascular risk reduction in hypertriglyceridemia, especially in patients with FHTG [ 55 , 56 ]. The results suggest that this molecule may be involved in the pathogenesis of FHTG and its measurement may be helpful for diagnosis (Fig.…”

GALNT2 regulates ANGPTL3 cleavage in cells and in vivo of mice

“…However, recent study also suggests that N-terminal domain of ANGPTL3 and cleavage defective ANGPTL3 have similar ability in LPL inhibition with or without its cofactor ANGTPL8 in vitro 36 . ANGPTL3 modulates HDL-C and LDL-C metabolism mainly through inhibiting EL 42,[49][50][51] . Galnt2 knocking down upregulates Angptl3 cleavage dramatically in mice, together with decreased levels of total cholesterol and HDL-C ( Fig.…”

“…ANGPTL3 modulates HDL-C and LDL-C metabolism mainly through inhibiting EL 42 , 49 – 51 . Galnt2 knocking down upregulates Angptl3 cleavage dramatically in mice, together with decreased levels of total cholesterol and HDL-C (Fig.…”

Hepatokines and metabolism: Deciphering communication from the liver

“…ANGPTL3 is proteolytically cleaved by proprotein convertases, which allows complex formation with ANGPTL8 to orchestrate the inhibition of LPL and the dysregulation of carbohydrate and lipid homeostasis [ 37 , 39 , 40 ]. Furthermore, inhibition of ANGPTL3 reduces VLDL lipid content and size in an endothelial lipase-dependent manner [ 41 ]. ANGPTL3 likely augments carbohydrate homeostasis by inducing lipolysis in adipose tissue [ 42 ], attenuating de novo lipogenesis [ 43 ], and upregulating ANGPTL4 expression [ 44 ], factors that result in decreased glucose uptake and insulin sensitivity.…”