title: Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice.
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.
authors.affiliation: Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX, 77381, USA.
authors.forename: Urvi
authors.initials: U
authors.lastname: Desai
authors.forename: E-Chiang
authors.initials: EC
authors.lastname: Lee
authors.forename: Kyu
authors.initials: K
authors.lastname: Chung
authors.forename: Cuihua
authors.initials: C
authors.lastname: Gao
authors.forename: Jason
authors.initials: J
authors.lastname: Gay
authors.forename: Billie
authors.initials: B
authors.lastname: Key
authors.forename: Gwenn
authors.initials: G
authors.lastname: Hansen
authors.forename: Dennis
authors.initials: D
authors.lastname: Machajewski
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Platt
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Sands
authors.forename: Matthias
authors.initials: M
authors.lastname: Schneider
authors.forename: Isaac
authors.initials: I
authors.lastname: Van Sligtenhorst
authors.forename: Adisak
authors.initials: A
authors.lastname: Suwanichkul
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Nat
authors.initials: N
authors.lastname: Wilganowski
authors.forename: June
authors.initials: J
authors.lastname: Wingert
authors.forename: Brian P
authors.initials: BP
authors.lastname: Zambrowicz
authors.forename: Greg
authors.initials: G
authors.lastname: Landes
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000096:biosynthesis; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D001798:Blood Proteins; D000960:Hypolipidemic Agents; D008055:Lipids; D008079:Lipoproteins, VLDL; D014280:Triglycerides