TY - JOUR
T1 - AAV1-LPL(S447X) gene therapy reduces hypertriglyceridemia in apoE2 knock in mice
AU - Rip, Jaap
AU - van Dijk, Ko Willems
AU - Sierts, Jeroen A.
AU - Kastelein, John J. P.
AU - Twisk, Jaap
AU - Kuivenhoven, Jan Albert
PY - 2006
Y1 - 2006
N2 - 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-LPL(S447X) 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-LPL(S447X) (n=6; 8 x 10(12) 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-LPL(S447X) 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
AB - 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-LPL(S447X) 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-LPL(S447X) (n=6; 8 x 10(12) 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-LPL(S447X) 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
U2 - https://doi.org/10.1016/j.bbalip.2006.08.008
DO - https://doi.org/10.1016/j.bbalip.2006.08.008
M3 - Article
C2 - 16990047
SN - 1388-1981
VL - 1761
SP - 1163
EP - 1168
JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
IS - 10
ER -