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 (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.