Highlights
- •Angptl3 silencing induced combined hypolipidemia in WT and obese mice.
- •Angptl3 silencing reduced plasma TG and LDL-C, but not HDL-C, in hCETP/ApoB-100 transgenic mice.
- •The low LDL-C from Angptl3 silencing is linked to LDLR in Apobec1−/−/ApoB-100 transgenic mice lacking LDLR.
- •ANGPTL3 deficiency in human hepatoma cells reduced nascent ApoB-100 secretion and increased LDL/VLDL uptake.
- •Reduced secretion and increased uptake of ApoB-containing lipoproteins contribute to the low LDL-C caused by ANGPTL3 deficiency.
Abstract
Background and aims
Angiopoietin-like 3 (ANGPTL3) has emerged as a key regulator of lipoprotein metabolism
in humans. Homozygous loss of ANGPTL3 function causes familial combined hypolipidemia characterized by low plasma levels
of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density
lipoprotein cholesterol (LDL-C). While known effects of ANGPTL3 in inhibiting lipoprotein
lipase and endothelial lipase contribute to the low TG and HDL-C, respectively, the
basis of low LDL-C remains unclear. Our aim was to explore the role of ANGPTL3 in
modulating plasma LDL-C.
Methods
We performed RNAi-mediated gene silencing of ANGPTL3 in five mouse models and in human hepatoma cells. We validated results by deleting
ANGPTL3 gene using the CRISPR/Cas9 genome editing system.
Results
RNAi-mediated Angptl3 silencing in mouse livers resulted in very low TG, HDL-C and LDL-C, a pattern similar
to the human phenotype. The effect was observed in wild-type and obese mice, while
in hCETP/apolipoprotein (Apo) B-100 double transgenic mice, the silencing decreased LDL-C and TG, but not HDL-C. In a
humanized mouse model (Apobec1−/− carrying human ApoB-100 transgene) deficient in the LDL receptor (LDLR), Angptl3 silencing had minimum effect on LDL-C, suggesting the effect being linked to LDLR.
This observation is supported by an additive effect on LDL-C between ANGPTL3 and PCSK9 siRNAs. ANGPTL3 gene deletion induced cellular long-chain TG and ApoB-100 accumulation with elevated
LDLR and LDLR-related protein (LRP) 1 expression. Consistent with this, ANGPTL3 deficiency by gene deletion or silencing reduced nascent ApoB-100 secretion and increased
LDL/VLDL uptake.
Conclusions
Reduced secretion and increased uptake of ApoB-containing lipoproteins may contribute
to the low LDL-C observed in mice and humans with genetic ANGPTL3 deficiency.
Keywords
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Article Info
Publication History
Published online: September 21, 2017
Accepted:
August 30,
2017
Received in revised form:
August 2,
2017
Received:
March 20,
2017
Identification
Copyright
© 2017 Elsevier B.V. All rights reserved.
