Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice
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DOI：
10.1073/pnas.0705041104
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发表时间：
2007-07-10
影响因子：
11.1
通讯作者：
Powell, David R.
中科院分区：
文献类型：
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作者：
Desai, Urvi;Lee, E-Chiang;Powell, David R.
我们利用基因敲除小鼠探索血管生成素样蛋白4(Angiopoietin-like-4，ANGPTL4)在脂质代谢中的作用，并制备具有药理活性的抗Angptl4单抗。ANGPTL4-/-小鼠的甘油三酯(TG)水平较低，这是由于极低密度脂蛋白(VLDL)清除增加和极低密度脂蛋白(VLDL)产生减少所致，并且胆固醇水平略低。此外，喂食高脂饮食的ANGPTL4/-哺乳小鼠和成年小鼠都显示出与肠道及其引流淋巴管和肠系膜淋巴结的脂肪肉芽肿性病变相关的生存能力降低。用抗ANGPTL4单抗14D12治疗C57BL/6J、ApoE-/-、LDLR-/-和db/db小鼠，概括了ANGPTL4-/-小鼠的脂质和组织病理学表型。这表明，敲除表型不仅反映了ANGPTL4基因的生理功能，而且还预测了在相关的人类疾病模型中用中和抗体抑制ANGPTL4蛋白的药理学后果。
We used gene knockout mice to explore the role of Angiopoietin-like-4 (Angptl4) in lipid metabolism as well as to generate antiAngptl4 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.