Atypical angiopoietin-like protein that regulates ANGPTL3
Atypical angiopoietin-like protein that regulates ANGPTL3
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DOI：
10.1073/pnas.1217552109
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发表时间：
2012-11-27
影响因子：
11.1
通讯作者：
Hobbs, Helen H.
中科院分区：
文献类型：
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作者：
Quagliarini, Fabiana;Wang, Yan;Hobbs, Helen H.
血管生成素样蛋白(Angiopoietin-like Proteins，ANGPTL)在脂质的运输和代谢中发挥重要作用。位于DOCK7内含子的Angptl3基因失活会导致极低的低密度脂蛋白-胆固醇(C)、高密度脂蛋白-C和甘油三酯(TAG)水平。我们发现了另一个ANGPTL家族成员ANGPTL8，它位于DOCK6的相应内含子中。该家族成员的一个变异(rs2278426，R59W)与三个人群中较低的血浆低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平相关。ANGPTL8在肝脏和脂肪组织中表达，在人体血浆中循环。在小鼠和人类中，ANGPTL8的表达通过禁食而减少，通过重新喂养而增加。为了研究这两个ANGPTL家族成员之间的功能关系，我们在小鼠肝脏中单独或与ANGPTL8一起在生理水平表达了Angptl3。单独表达Angptl3的小鼠的血浆TAG水平没有变化，而与ANGPTL8共同表达会导致高甘油三酯血症，尽管循环中的Angptl3减少。ANGPTL8与这些小鼠血浆中的Angptl3的N-末端结构域共沉淀。在培养的肝细胞中，ANGPTL8的表达增加了培养液中N-末端Angptl3的出现，提示ANGPTL8可能激活了Angptl3。与这种情况一致，在Angptl3(-/-)小鼠中表达ANGPTL8未能促进高甘油三酯血症。因此，ANGPTL8，一个通过复制祖先DOCK基因而产生的Angptl3的旁系基因，通过控制其前体或其他ANGPTL的激活来调节餐后标签和脂肪酸代谢。抑制ANGPTL8为降低血浆脂蛋白水平提供了新的治疗策略。
Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3(-/-) mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.