Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation.
Arterioscler Thromb Vasc Biol
; 25(10): 2143-50, 2005 Oct.
Article
em En
| MEDLINE
| ID: mdl-16002740
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Hipertrigliceridemia
/
Mutação Puntual
/
Lipase Lipoproteica
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article