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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
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Departments of *Pharmaceutical Biology, Biotherapeutics, and Genetics, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX, 77381
Communicated by C. Thomas Caskey, University of Texas-Houston Health Science Center, Houston, TX, May 30, 2007 (received for review March 13, 2007)
We used gene knockout mice to explore the role of Angiopoietin-like-4 (Angptl4) in lipid metabolism as well as to generate anti-Angptl4 mAbs with pharmacological activity. Angptl4 –/– mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 –/– suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE –/–, LDLr –/–, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 –/– mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease.
monoclonal antibody | mouse | triglycerides | cholesterol
Present address: Agdia Incorporated, Elkhart, IN 46514.
Conflict of interest statement: All authors are or have been employed by Lexicon Pharmaceuticals, Inc., and may own publicly traded stock in Lexicon. The research was supported by Lexicon.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705041104/DC1.
¶To whom correspondence should be addressed. E-mail: dpowell{at}lexpharma.com
© 2007 by The National Academy of Sciences of the USA
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