Intravenous injection of apolipoprotein A-V reconstituted high-density lipoprotein decreases hypertriglyceridemia in apoav-/- mice and requires glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.
OBJECTIVE
Apolipoprotein A-V (apoA-V), a minor protein associated with lipoproteins, has a major effect on triacylglycerol (TG) metabolism. We investigated whether apoA-V complexed with phospholipid in the form of a reconstituted high-density lipoprotein (rHDL) has potential utility as a therapeutic agent for treatment of hypertriglyceridemia (HTG) when delivered intravenously.


RESULTS
Intravenous injection studies were performed in genetically engineered mouse models of severe HTG, including apoav-/- and gpihbp1-/- mice. Administration of apoA-V rHDL to hypertriglyceridemic apoav-/- mice resulted in a 60% reduction in plasma TG concentration after 4 hours. This decline can be attributed to enhanced catabolism/clearance of very-low-density lipoprotein (VLDL), where VLDL TG and cholesterol were reduced ≈60%. ApoA-V that associated with VLDL after injection was also rapidly cleared. Site-specific mutations in the heparin-binding region of apoA-V (amino acids 186 to 227) attenuated apoA-V rHDL TG-lowering activity by 50%, suggesting that this sequence element is required for optimal TG-lowering activity in vivo. Unlike apoav-/- mice, injection of apoA-V rHDL into gpihbp1-/- mice had no effect on plasma TG levels, and apoA-V remained associated with plasma VLDL.


CONCLUSIONS
Intravenously injected apoA-V rHDL significantly lowers plasma TG in an apoA-V deficient mouse model. Its intravenous administration may have therapeutic benefit in human subjects with severe HTG, especially in cases involving apoA-V variants associated with HTG.
Center for Prevention of Obesity, Cardiovascular Disease and Diabetes, Children's Hospital Oakland Research Institute, Oakland, Calif, USA.
Xiao
X
Shu
Lisa
L
Nelbach
Michael M
MM
Weinstein
Braydon L
BL
Burgess
Jennifer A
JA
Beckstead
Stephen G
SG
Young
Robert O
RO
Ryan
Trudy M
TM
Forte
D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000172:deficiency* / Q000235:genetics; D001054:Apolipoproteins A / Q000008:administration & dosage* / Q000097:blood; D001665:Binding Sites; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006493:Heparin / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000097:blood; D007275:Injections, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D015415:Biomarkers; C472779:GPI-HBP1 protein, mouse; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D014280:Triglycerides; D006493:Heparin