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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.

SUBMITTER: Desai U 

PROVIDER: S-EPMC1913890 | biostudies-other | 2007 Jul

REPOSITORIES: biostudies-other

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

Desai Urvi U   Lee E-Chiang EC   Chung Kyu K   Gao Cuihua C   Gay Jason J   Key Billie B   Hansen Gwenn G   Machajewski Dennis D   Platt Kenneth A KA   Sands Arthur T AT   Schneider Matthias M   Van Sligtenhorst Isaac I   Suwanichkul Adisak A   Vogel Peter P   Wilganowski Nat N   Wingert June J   Zambrowicz Brian P BP   Landes Greg G   Powell David R DR  

Proceedings of the National Academy of Sciences of the United States of America 20070703 28

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 lipogranulomat  ...[more]