Angiopoietin-Like Protein 4 Is a High-Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type-2 Diabetic Patients
Angiopoietin-Like Protein 4 Is a High-Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type-2 Diabetic Patients
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血管生成素样蛋白 4 是一种高密度脂蛋白 (HDL) 成分，与非糖尿病参与者和 2 型糖尿病患者的 HDL 代谢和功能有关。
DOI：
10.1161/jaha.117.005973
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发表时间：
2017-06-01
影响因子：
5.4
通讯作者：
Feng, Ying-Mei
中科院分区：
文献类型：
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作者：
Yang, Long-Yan;Yu, Cai-Guo;Feng, Ying-Mei
背景 - 血管生成素样蛋白4（ANGPTL4）是一种脂蛋白脂肪酶（LPL）抑制剂，存在于高密度脂蛋白（HDL）中。然而，HDL中的ANGPTL4是否会影响2型糖尿病（T2DM）中HDL的代谢和功能尚不明确。
方法与结果 - 对非糖尿病参与者（n = 201，女性占68.7%）和T2DM患者（n = 185，女性占66.5%）的循环及HDL中的ANGPTL4水平进行了定量。从非糖尿病对照者和T2DM患者中分离出HDL，以评估胆固醇流出，或使其与内皮脂肪酶（EL）过表达的HEK293细胞在体外进行EL水解。分别在非糖尿病参与者和糖尿病患者中分析了HDL中ANGPTL4与HDL成分及功能之间的关联。分别对ANGPTL4 +/+和ANGPTL4 -/-小鼠的血浆或HDL进行胆固醇流出或EL水解实验。T2DM患者血浆和HDL中的ANGPTL4水平分别比非糖尿病对照者高1.7倍和2.0倍（P < 0.0001）。多变量分析表明，在非糖尿病对照者中，HDL中ANGPTL4水平每增加1倍，胆固醇流出变化为 +0.27%（P = 0.03），载脂蛋白A - I增加 +0.06μg/mL（P = 0.09），血清淀粉样蛋白A减少 -9.41μg/L（P = 0.02）。在T2DM患者中，相应的估计值为胆固醇流出 -0.06%（P = 0.10），载脂蛋白A - I减少 -0.06μg/mL（P = 0.38），血清淀粉样蛋白A增加 +3.64μg/L（P = 0.72）。与ANGPTL4 +/+同窝小鼠相比，从ANGPTL4 -/-小鼠中分离出的HDL显示出EL加速水解和胆固醇流出减少。
结论 - 从机制上讲，HDL中的ANGPTL4保护HDL免受水解。由于T2DM中循环ANGPTL4水平升高，HDL中的ANGPTL4水平虽升高，但对EL的抑制作用受损，导致HDL水解增加和功能障碍。
Background-ANGPTL4 (angiopoietin-like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high-density lipoprotein (HDL). However, it is not defined whether ANGPTL4 in HDLs could affect HDL metabolism and function in type 2 diabetes mellitus (T2DM).Methods and Results-ANGPTL4 levels in the circulation and HDLs were quantified in nondiabetic participants (n = 201, 68.7% females) and T2DM patients (n = 185, 66.5% females). HDLs were isolated from nondiabetic controls and T2DM patients to assess cholesterol efflux or subjected to endothelial lipase (EL)-overexpressed HEK293 cells for EL hydrolysis in vitro. The association between ANGPTL4 in HDLs and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDLs of ANGPTL4+/+ and ANGPTL4-/- mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL4 levels in the plasma and HDLs were 1.7- and 2.0-fold higher in T2DM patients than nondiabetic controls, respectively (P < 0.0001). Multivariable analysis demonstrated that per 1 doubling increase of ANGPTL4 levels in HDLs, the changes amounted to +0.27% cholesterol efflux (P = 0.03), + 0.06 mu g/mL apolipoprotein A-I (P = 0.09) and -9.41 mu g/L serum amyloid A (P = 0.02) in nondiabetic controls. In T2DM patients, the corresponding estimates were -0.06% cholesterol efflux (P = 0.10), -0.06 mu g/mL apolipoprotein A-I (P = 0.38), and + 3.64 mu g/L serum amyloid A (P = 0.72). HDLs isolated from ANGPTL4-/- mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL4+/+ littermates.Conclusions-Physically, ANGPTL4 in HDLs protected HDLs from hydrolysis. Resulting from increased circulating ANGPTL4 levels in T2DM, ANGPTL4 levels in HDLs were elevated but with compromised inhibitory effect on EL, leading to increased HDL hydrolysis and dysfunction.