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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2143.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Complete Rescue of Lipoprotein Lipase–Deficient Mice by Somatic Gene Transfer of the Naturally Occurring LPL^S447X Beneficial Mutation

Colin J.D. Ross; Guoqing Liu; Jan Albert Kuivenhoven; Jaap Twisk; Jaap Rip; Willemijn van Dop; Katherine J.D. Ashbourne Excoffon; Suzanne M.E. Lewis; John J. Kastelein; Michael R. Hayden

From the Department of Medical Genetics (C.J.D.R., G.L., K.J.D.A.E., S.M.E.L., M.R.H.), University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, Canada; the Department of Experimental Vascular Medicine (J.A.K., J.R., W.v.D., J.J.K.), University of Amsterdam, Academic Medical Center, the Netherlands; Amsterdam Molecular Therapeutics (J.T.), the Netherlands.

Correspondence to Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, 950 West 28th Ave, Vancouver, BC, Canada V5Z-4H4. E-mail mrh{at}cmmt.ubc.ca

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

We investigated the in vivo mechanism by which naturally occurring LPL^S447X variant improves the lipid profile of S447X carriers by comparing human LPL^S447X to LPL^WT in newborn LPL^–/– mice. LPL^WT prolonged newborn survival to 21 days. In contrast, the increased catalytic activity of LPL^S447X completely rescued LPL^–/– mice to adulthood.

Key Words: beneficial mutation • chylomicronemia • lipoprotein lipase • type 1 hyperlipoproteinemia

Related Article:

Gain-of-Function Mutations and Therapeutic Implications: Lipoprotein Lipase S447X to the Rescue

Daniel J. Rader
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