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Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
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Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
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Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
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Journal Article
Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
2007
Overview
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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ Antibodies, Blocking - administration & dosage
/ Antibodies, Blocking - biosynthesis
/ Antibodies, Monoclonal - administration & dosage
/ Antibodies, Monoclonal - biosynthesis
/ Fasting
/ genes
/ Hypolipidemic Agents - administration & dosage
/ Hypolipidemic Agents - metabolism
/ Hypolipidemic Agents - therapeutic use
/ Lesions
/ Lipids
/ Lipids - antagonists & inhibitors
/ Lipoproteins, VLDL - antagonists & inhibitors
/ Male
/ Mice
/ Rodents
/ suckling
/ Triglycerides - antagonists & inhibitors
