Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1950200 | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | 2006 | 6 Pages |
Abstract
Intramuscular (IM) application of adeno-associated virus serotype 1 (AAV1) for the delivery of human lipoprotein lipase (hLPL) was previously shown efficacious in mice with chylomicronemia. The current study addresses whether AAV1-LPLS447X can reduce elevated triglyceride (TG) levels in mice with attenuated clearance of TG-rich remnant particles. Methods. Female mice, expressing human apoE2 but deficient for endogenous apoE (apoE2KI) received IM injections of AAV1-LPLS447X (n = 6; 8 Ã 1012 gc/kg; 4-sites) or PBS (n = 5). Following lipid monitoring, the mice were challenged with intravenous Intralipid injections, and sacrificed 3 months after treatment. Results. In the mice that received LPL gene therapy, a marked increase of post-heparin hLPL protein levels (averaging 517 ± 277 ng/mL vs. 4 ± 3 ng/mL in apoE2KI-untreated) induced 20% reductions of fasting plasma TG levels (p < 0.05). This was accompanied by two-fold increased TG clearance rates after Intralipid administration at 6 weeks after treatment (p < 0.05). Post-mortem analyses revealed increased levels of TG (2-fold, p < 0.005) and cholesterol (1.7-fold, p < 0.001) in the treated muscles. Conclusions. IM application of AAV1-LPLS447X is effective in reducing TG levels in a mouse model for type III dyslipidemia. Thus, hypertriglyceridemia caused by attenuated uptake of TG-rich lipoproteins can be alleviated by increasing lipolytic function of the skeletal muscle tissue.
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Authors
Jaap Rip, Ko Willems van Dijk, Jeroen A. Sierts, John J.P. Kastelein, Jaap Twisk, Jan Albert Kuivenhoven,