Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

  • Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11766-71. doi: 10.1073/pnas.0705041104.
Urvi Desai  1 ,  E-Chiang Lee ,  Kyu Chung ,  Cuihua Gao ,  Jason Gay ,  Billie Key ,  Gwenn Hansen ,  Dennis Machajewski ,  Kenneth A Platt ,  Arthur T Sands ,  Matthias Schneider ,  Isaac Van Sligtenhorst ,  Adisak Suwanichkul ,  Peter Vogel ,  Nat Wilganowski ,  June Wingert ,  Brian P Zambrowicz ,  Greg Landes ,  David R Powell
Affiliations
  • 1. Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX, 77381, USA.
PMID: 17609370 DOI: 10.1073/pnas.0705041104
Abstract

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.