TY - JOUR
T1 - Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation
AU - Ross, Colin J. D.
AU - Liu, Guoqing
AU - Kuivenhoven, Jan Albert
AU - Twisk, Jaap
AU - Rip, Jaap
AU - van Dop, Willemijn
AU - Excoffon, Katherine J. D. Ashbourne
AU - Lewis, Suzanne M. E.
AU - Kastelein, John J.
AU - Hayden, Michael R.
PY - 2005
Y1 - 2005
N2 - The naturally occurring human lipoprotein lipase S447X variant (LPLS447X) exemplifies a gain-of function mutation with significant benefits including decreased plasma triglycerides (TG), increased high-density lipoprotein (HDL) cholesterol, and reduced risk of coronary artery disease. The S447X variant may be associated with higher LPL catalytic activity; however, in vitro data supporting this hypothesis are contradictory. We wanted to investigate the in vivo mechanism by which the LPLS447X variant improves the lipid profile of S447X carriers. We conducted a functional assessment of human (LPLX)-X-S447 compared with LPLWT in mice. LPL variants were compared in the absence of endogenous mouse LPL in newborn LPL-/- mice by adenoviral-mediated gene transfer. LPL-/- mice normally exhibit severe hypertriglyceridemia and die within 48 hours of birth. LPLWT gene transfer prolonged the survival of mice up to 21 days. In contrast, LPLS447X completely rescued 95% of the mice to adulthood and increased LPL catalytic activity in postheparin plasma 2.1-fold compared with LPLWT at day 3 ( P = 0.003). LPLS447X also reduced plasma TG 99% from baseline ( P <0.001), 2-fold more than LPLWT, ( P <0.01) and increased plasma HDL cholesterol 2.9-fold higher than LPLWT ( P <0.01). These data provide in vivo evidence that the increased catalytic activity of LPLS447X improves plasma TG clearance and increases the HDL cholesterol pool compared with LPLWT
AB - The naturally occurring human lipoprotein lipase S447X variant (LPLS447X) exemplifies a gain-of function mutation with significant benefits including decreased plasma triglycerides (TG), increased high-density lipoprotein (HDL) cholesterol, and reduced risk of coronary artery disease. The S447X variant may be associated with higher LPL catalytic activity; however, in vitro data supporting this hypothesis are contradictory. We wanted to investigate the in vivo mechanism by which the LPLS447X variant improves the lipid profile of S447X carriers. We conducted a functional assessment of human (LPLX)-X-S447 compared with LPLWT in mice. LPL variants were compared in the absence of endogenous mouse LPL in newborn LPL-/- mice by adenoviral-mediated gene transfer. LPL-/- mice normally exhibit severe hypertriglyceridemia and die within 48 hours of birth. LPLWT gene transfer prolonged the survival of mice up to 21 days. In contrast, LPLS447X completely rescued 95% of the mice to adulthood and increased LPL catalytic activity in postheparin plasma 2.1-fold compared with LPLWT at day 3 ( P = 0.003). LPLS447X also reduced plasma TG 99% from baseline ( P <0.001), 2-fold more than LPLWT, ( P <0.01) and increased plasma HDL cholesterol 2.9-fold higher than LPLWT ( P <0.01). These data provide in vivo evidence that the increased catalytic activity of LPLS447X improves plasma TG clearance and increases the HDL cholesterol pool compared with LPLWT
U2 - https://doi.org/10.1161/01.ATV.0000176971.27302.b0
DO - https://doi.org/10.1161/01.ATV.0000176971.27302.b0
M3 - Article
C2 - 16002740
SN - 1079-5642
VL - 25
SP - 2143
EP - 2150
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 10
ER -