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

Desai U,Lee EC,Chung K,Gao C,Gay J,Key B,Hansen G,Machajewski D,Platt KA,Sands AT,Schneider M,Van Sligtenhorst I,Suwanichkul A,Vogel P,Wilganowski N,Wingert J,Zambrowicz BP,Landes G,Powell DR

doi

10.1073/pnas.0705041104

subject

Has Abstract

pub_date

2007-07-10 00:00:00

pages

11766-71

issue

28

eissn

0027-8424

issn

1091-6490

pii

0705041104

journal_volume

104

pub_type

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