This Article Full Text Full Text (PDF) All Versions of this Article: 25/10/2143    most recent 01.ATV.0000176971.27302.b0v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ross, C. J.D. Articles by Hayden, M. R. Search for Related Content PubMed PubMed Citation Articles by Ross, C. J.D. Articles by Hayden, M. R. Related Collections Related Article

(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
Arterioscler. Thromb. Vasc. Biol. 2005 25: 2018-2019. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				X. Xian, T. Liu, J. Yu, Y. Wang, Y. Miao, J. Zhang, Y. Yu, C. Ross, J. M. Karasinska, M. R. Hayden, et al. Presynaptic Defects Underlying Impaired Learning and Memory Function in Lipoprotein Lipase-Deficient Mice J. Neurosci., April 8, 2009; 29(14): 4681 - 4685. [Abstract] [Full Text] [PDF]

				Y Wang, L Sternfeld, F Yang, J A Rodriguez, C Ross, M R Hayden, F Carriere, G Liu, W Hofer, and I Schulz Enhanced susceptibility to pancreatitis in severe hypertriglyceridaemic lipoprotein lipase-deficient mice and agonist-like function of pancreatic lipase in pancreatic cells Gut, March 1, 2009; 58(3): 422 - 430. [Abstract] [Full Text] [PDF]

				X. Zhang, R. Qi, X. Xian, F. Yang, M. Blackstein, X. Deng, J. Fan, C. Ross, J. Karasinska, M. R. Hayden, et al. Spontaneous Atherosclerosis in Aged Lipoprotein Lipase-Deficient Mice With Severe Hypertriglyceridemia on a Normal Chow Diet Circ. Res., February 1, 2008; 102(2): 250 - 256. [Abstract] [Full Text] [PDF]

				G. Yuan, K. Z. Al-Shali, and R. A. Hegele Hypertriglyceridemia: its etiology, effects and treatment Can. Med. Assoc. J., April 10, 2007; 176(8): 1113 - 1120. [Abstract] [Full Text] [PDF]

				J. Wang, X. Xian, W. Huang, L. Chen, L. Wu, Y. Zhu, J. Fan, C. Ross, M. R. Hayden, and G. Liu Expression of LPL in Endothelial-Intact Artery Results in Lipid Deposition and Vascular Cell Adhesion Molecule-1 Upregulation in Both LPL and ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 197 - 203. [Abstract] [Full Text] [PDF]

				J. Rip, M. C. Nierman, C. J. Ross, J. W. Jukema, M. R. Hayden, J. J.P. Kastelein, E. S.G. Stroes, and J. A. Kuivenhoven Lipoprotein Lipase S447X: A Naturally Occurring Gain-of-Function Mutation Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1236 - 1245. [Abstract] [Full Text] [PDF]

				R. A. Hegele, C. J.D. Ross, J. Twisk, J. A. Kuivenhoven, J. Rip, J. J. Kastelein, and M. R. Hayden Gene therapy with lipoprotein lipase variant S447X. Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): e25 - e25. [Full Text] [PDF]

				D. J. Rader Gain-of-Function Mutations and Therapeutic Implications: Lipoprotein Lipase S447X to the Rescue Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2018 - 2019. [Full Text] [PDF]