Lipid-lowering Effects of Anti-angiopoietin-like 4 Antibody Recapitulate the Lipid Phenotype Found in Angiopoietin-like 4 Knockout Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Jul 5

PMID 17609370

Citations 101

Authors

Urvi Desai

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

Soon will be listed here.

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.

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