title: 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.
  
  
  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: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors: Vineeta
authors: V
authors: Sharma
authors: Jennifer A
authors: JA
authors: Beckstead
authors: Jens B
authors: JB
authors: Simonsen
authors: Lisa
authors: L
authors: Nelbach
authors: Gordon
authors: G
authors: Watson
authors: Trudy M
authors: TM
authors: Forte
authors: Robert O
authors: RO
authors: Ryan
mesh_terms: D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000172:deficiency* / Q000235:genetics; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood; D000229:Dependovirus / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics / Q000628:therapy*; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012720:Severity of Illness Index; D013997:Time Factors; D014161:Transduction, Genetic; D014280:Triglycerides / Q000097:blood
chemical_list: C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D015415:Biomarkers; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D002784:Cholesterol