Gene Transfer of Apolipoprotein A-V Improves the Hypertriglyceridemic Phenotype of apoa5 (−/−) mice

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 1×1012 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-&bgr;-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. Conclusion—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.

[1]  Xuan Gao,et al.  Influence of apolipoprotein A-V on hepatocyte lipid droplet formation. , 2012, Biochemical and biophysical research communications.

[2]  D. Harats,et al.  Apolipoprotein A-V modulates multiple atherogenic mechanisms in a mouse model of disturbed clearance of triglyceride-rich lipoproteins. , 2012, Atherosclerosis.

[3]  T. Forte,et al.  Apolipoprotein A-V dependent modulation of plasma triacylglycerol: a puzzlement. , 2012, Biochimica et biophysica acta.

[4]  G. Olivecrona,et al.  Apolipoprotein A-V; a potent triglyceride reducer. , 2011, Atherosclerosis.

[5]  S. Young,et al.  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 , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[6]  V. Salomaa,et al.  Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia , 2010, Nature Genetics.

[7]  M. Hayden,et al.  Plasma apolipoprotein AV levels in mice are positively associated with plasma triglyceride levels Published, JLR Papers in Press, January 13, 2009. , 2009, Journal of Lipid Research.

[8]  B. Staels,et al.  Atheroprotective Effect of Human Apolipoprotein A5 in a Mouse Model of Mixed Dyslipidemia , 2008, Circulation research.

[9]  P. Moulin,et al.  Association of APOA5 -1131T>C and S19W gene polymorphisms with both mild hypertriglyceridemia and hyperchylomicronemia in type 2 diabetic patients. , 2008, Clinica chimica acta; international journal of clinical chemistry.

[10]  P. Talmud,et al.  The functional interaction on in vitro gene expression of APOA5 SNPs, defining haplotype APOA52, and their paradoxical association with plasma triglyceride but not plasma apoAV levels. , 2008, Biochimica et biophysica acta.

[11]  S. Bertolini,et al.  Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A‐V deficiency due to a novel mutation in the APOA5 gene , 2008, Journal of internal medicine.

[12]  T. Forte,et al.  Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice Published, JLR Papers in Press, December 3, 2007. , 2008, Journal of Lipid Research.

[13]  T. Forte,et al.  Apolipoprotein A-V association with intracellular lipid dropletss⃞ Published, JLR Papers in Press, April 25, 2007. , 2007, Journal of Lipid Research.

[14]  D. Rader,et al.  Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent , 2007, Cardiovascular Diabetology.

[15]  D. Rader,et al.  Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent , 2007 .

[16]  D. Rader,et al.  Complete Prevention of Atherosclerosis in ApoE-Deficient Mice by Hepatic Human ApoE Gene Transfer With Adeno-Associated Virus Serotypes 7 and 8 , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[17]  Le-ming Fan,et al.  A genetic variant c.553G > T in the apolipoprotein A5 gene is associated with an increased risk of coronary artery disease and altered triglyceride levels in a Chinese population. , 2006, Atherosclerosis.

[18]  Theresa A. Storm,et al.  Liver Transduction with Recombinant Adeno-Associated Virus Is Primarily Restricted by Capsid Serotype Not Vector Genotype , 2006, Journal of Virology.

[19]  L. Pennacchio,et al.  Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. , 2005, The Journal of clinical investigation.

[20]  A. Boodhoo,et al.  The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. , 2005, Clinical chemistry.

[21]  A. Cantafora,et al.  Inherited Apolipoprotein A-V Deficiency in Severe Hypertriglyceridemia , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[22]  M. Nieminen,et al.  APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease: results from the LOCAT study. , 2004, Journal of lipid research.

[23]  K. Chien,et al.  A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia. , 2003, Human molecular genetics.

[24]  C. Kay,et al.  Structure-function studies of human apolipoprotein A-V: a regulator of plasma lipid homeostasis. , 2003, Biochemistry.

[25]  Jonathan C. Cohen,et al.  Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. , 2002, Human molecular genetics.

[26]  Lili Wang,et al.  Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Jonathan C. Cohen,et al.  An Apolipoprotein Influencing Triglycerides in Humans and Mice Revealed by Comparative Sequencing , 2001, Science.

[28]  M. Fowkes,et al.  AAV8-mediated gene therapy prevents induced biochemical attacks of acute intermittent porphyria and improves neuromotor function. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  I. Graham,et al.  Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E , 2002, Gene Therapy.

[30]  P. Reitsma,et al.  Apolipoprotein A-V A NOVEL APOLIPOPROTEIN ASSOCIATED WITH AN EARLY PHASE OF LIVER REGENERATION* , 2001 .

[31]  K. Kinzler,et al.  A simplified system for generating recombinant adenoviruses. , 1998, Proceedings of the National Academy of Sciences of the United States of America.