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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 12; pp. 2504 - 2509
• Main Authors: Shu, Xiao, Nelbach, Lisa, Weinstein, Michael M., Burgess, Braydon L., Beckstead, Jennifer A., Young, Stephen G., Ryan, Robert O., Forte, Trudy M.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoprotein A-V; Apolipoproteins - deficiency; Apolipoproteins - genetics; Apolipoproteins A - administration & dosage; Apolipoproteins A - blood; Atherosclerosis (general aspects, experimental research); Binding Sites; Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Blood coagulation. Blood cells; Cardiology. Vascular system; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Down-Regulation; Fundamental and applied biological sciences. Psychology; Heparin - administration & dosage; Heparin - metabolism; Humans; Hypertriglyceridemia - drug therapy; Hypertriglyceridemia - genetics; Hypertriglyceridemia - metabolism; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - blood; Injections, Intravenous; Lipoproteins, HDL - administration & dosage; Lipoproteins, HDL - blood; Lipoproteins, VLDL - blood; Male; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Mutagenesis, Site-Directed; Mutation; Platelet; Receptors, Lipoprotein - genetics; Receptors, Lipoprotein - metabolism; Recombinant Proteins - administration & dosage; Time Factors; Triglycerides - blood; apolipoproteins; Intravenous administration; Rodentia; Metabolic diseases; Lipids; Cardiovascular disease; Hyperlipoproteinemia; Lipoprotein; Triglyceride; Enzymopathy; Vascular disease; Apolipoprotein A; Binding protein; Vertebrata; Mammalia; Mouse; Hypertriglyceridemia; Animal; Atherosclerosis; Dyslipemia; lipoproteins
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.110.210815

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. METHODS AND 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. CONCLUSION—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.