Complete Rescue of Lipoprotein Lipase–Deficient Mice by Somatic Gene Transfer of the Naturally Occurring LPL Beneficial Mutation

The naturally occurring human lipoprotein lipase S447X variant (LPL) 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 LPL variant improves the lipid profile of S447X carriers. We conducted a functional assessment of human LPL compared with LPL 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. LPL gene transfer prolonged the survival of mice up to 21 days. In contrast, LPL completely rescued 95% of the mice to adulthood and increased LPL catalytic activity in postheparin plasma 2.1-fold compared with LPL at day 3 (P 0.003). LPL also reduced plasma TG 99% from baseline (P 0.001), 2-fold more than LPL, (P 0.01) and increased plasma HDL cholesterol 2.9-fold higher than LPL (P 0.01). These data provide in vivo evidence that the increased catalytic activity of LPL improves plasma TG clearance and increases the HDL cholesterol pool compared with LPL. (Arterioscler Thromb Vasc Biol. 2005;25:2143-2150.)