Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol

Atherosclerosis. 2018 Jan:268:196-206. doi: 10.1016/j.atherosclerosis.2017.08.031. Epub 2017 Sep 21.

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: ANGPTL3; Angiopoietin-like protein 3; Cholesterol; HDL; High-density lipoprotein; LDL; LDL receptor; LDLR; Lipoprotein; Low-density lipoprotein; Triglycerides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins / deficiency
  • Angiopoietin-like Proteins / genetics
  • Angiopoietin-like Proteins / metabolism*
  • Animals
  • Apolipoprotein B-100 / genetics
  • Apolipoprotein B-100 / metabolism
  • Biomarkers / blood
  • CRISPR-Associated Protein 9 / genetics
  • CRISPR-Associated Protein 9 / metabolism
  • CRISPR-Cas Systems
  • Cholesterol Ester Transfer Proteins / genetics
  • Cholesterol Ester Transfer Proteins / metabolism
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood*
  • Down-Regulation
  • Gene Editing / methods
  • Hep G2 Cells
  • Humans
  • Liver / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / blood
  • Obesity / genetics
  • Proprotein Convertase 9 / genetics
  • Proprotein Convertase 9 / metabolism
  • RNA Interference
  • Receptors, LDL / deficiency
  • Triglycerides / blood

Substances

  • ANGPTL3 protein, human
  • APOB protein, human
  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins
  • Angptl3 protein, mouse
  • Apolipoprotein B-100
  • Biomarkers
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Receptors, LDL
  • Triglycerides
  • CRISPR-Associated Protein 9
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9