Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids
Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids
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DOI：
10.1194/jlr.ra120000781
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发表时间：
2020-08-01
影响因子：
6.5
通讯作者：
Konrad, Robert J.
中科院分区：
文献类型：
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作者：
Chen, Yan Q.;Pottanat, Thomas G.;Konrad, Robert J.
血管生成素样蛋白（ANGPTL）8与代谢综合征有关，据报道可通过未知机制调节脂肪FA摄取。在这里，我们研究了ANGPTL 8与ANGPTL 3或ANGPTL 4的复合物形成如何随喂养而变化以调节LPL。在人血清中，ANGPTL 3/8和ANGPTL 4/8复合物均在餐后增加，与HDL呈负相关，与所有其他代谢综合征标志物呈正相关。ANGPTL 3/8也与LDL-C呈正相关，并阻断LPL促进的肝细胞VLDL-C摄取。ANGPTL 3/8的LPL抑制活性比ANGPTL 3的LPL抑制活性强>100倍，并且ANGPTL 4/8的LPL抑制活性比ANGPTL 4的LPL抑制活性弱>100倍。复合物之间的抑制活性和竞争实验的定量分析提出了一种模型，其中局部ANGPTL 4/8阻断循环ANGPTL 3/8和局部ANGPTL 4两者的LPL抑制活性，允许在进食状态期间脂质螯合到脂肪而不是肌肉中。支持该模型，胰岛素增加肝细胞的ANGPTL 3/8分泌和脂肪细胞的ANGPTL 4/8分泌。这些结果表明，禁食期间的低ANGPTL 8水平使得脂肪组织中ANGPTL 4介导的LPL抑制能够使脂肪FA摄取最小化。在进食期间，增加的ANGPTL 8通过循环ANGPTL 3/8增加ANGPTL 3对肌肉中LPL的抑制，同时通过局部ANGPTL 4/8减少ANGPTL 4对脂肪组织中LPL的抑制，从而增加脂肪组织中的FA摄取。过多的热量摄入可能使该系统向后一种情况转变，可能诱发代谢综合征。
Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.