Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation.
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 LPLS447X 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.
Ross
Colin J D
CJ
Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, Canada.
Liu
Guoqing
G
Kuivenhoven
Jan Albert
JA
Twisk
Jaap
J
Rip
Jaap
J
van Dop
Willemijn
W
Excoffon
Katherine J D Ashbourne
KJ
Lewis
Suzanne M E
SM
Kastelein
John J
JJ
Hayden
Michael R
MR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D008076:Cholesterol, HDL / Q000097:blood; D006224:Cricetinae; D005298:Fertility; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics / Q000628:therapy*; D007774:Lactation; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017354:Point Mutation; D012333:RNA, Messenger / Q000032:analysis; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D012333:RNA, Messenger; D014280:Triglycerides; D008071:Lipoprotein Lipase