Gene transfer of apolipoprotein A-V improves the hypertriglyceridemic phenotype of apoa5 (-/-) mice.

Abstract

OBJECTIVE:

Apolipoprotein (apo) A-V is a low abundance protein with a profound influence on plasma triacylglycerol levels. In human populations, single nucleotide polymorphisms and mutations in APOA5 positively correlate with hypertriglyceridemia. As an approach to preventing the deleterious effects of chronic hypertriglyceridemia, apoA-V gene therapy has been pursued.

METHODS AND RESULTS:

Recombinant adeno-associated virus (AAV) 2/8 harboring the coding sequence for human apoA-V or a control AAV2/8 was transduced into hypertriglyceridemic apoa5 (-/-) mice. After injection of 1×10(12) viral genome AAV2/8-apoA-V, maximal plasma levels of apoA-V protein were achieved at 3 to 4 weeks, after which the concentration slowly declined. Complementing the appearance of apoA-V was a decrease (50±6%) in plasma triacylglycerol content compared with apoa5 (-/-) mice treated with AAV2/8-β-galactosidase. After 8 weeks the mice were euthanized and plasma lipoproteins separated. AAV2/8-apoA-V-transduced mice displayed a dramatic reduction in very low-density lipoprotein triacylglycerol content. Vector generated apoA-V in plasma associated with both very low-density lipoprotein and high-density lipoprotein fractions.

CONCLUSIONS:

Taken together, the data show that gene transfer of apoA-V improves the severe hypertriglyceridemia phenotype of apoa5 (-/-) mice. Given the prevalence of hypertriglyceridemia, apoA-V gene therapy offers a potential strategy for maintenance of plasma triacylglycerol homeostasis.

• Authors: Vineeta Sharma, Jennifer A Beckstead, Jens B Simonsen, Lisa Nelbach, Gordon Watson, Trudy M Forte, Robert O Ryan
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 3 Pg. 474-80 (Mar 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23329134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• APOA5 protein, human
• Apoa5 protein, mouse
• Apolipoprotein A-V
• Apolipoproteins
• Apolipoproteins A
• Biomarkers
• Lipoproteins, HDL
• Lipoproteins, VLDL
• Triglycerides
• Cholesterol

Topics

• Animals
• Apolipoprotein A-V
• Apolipoproteins (deficiency, genetics)
• Apolipoproteins A (blood, genetics, metabolism)
• Biomarkers (blood)
• Cholesterol (blood)
• Dependovirus (genetics)
• Genetic Predisposition to Disease
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Hypertriglyceridemia (blood, genetics, therapy)
• Lipoproteins, HDL (blood)
• Lipoproteins, VLDL (blood)
• Male
• Mice
• Mice, Knockout
• Phenotype
• Severity of Illness Index
• Time Factors
• Transduction, Genetic
• Triglycerides (blood)