Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins
Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins
复制标题
DOI：
10.1074/jbc.273.28.17483
复制
发表时间：
1998-07-10
影响因子：
4.8
通讯作者：
Mahley, RW
中科院分区：
文献类型：
--
作者：
Huang, YD;Liu, XQ;Mahley, RW
载脂蛋白 (apo) E2 通常与人类低水平的低密度脂蛋白 (LDL) 胆固醇和高水平的血浆甘油三酯有关。表达 apoE2 的小鼠的 LDL 水平也较低。为了评估LDL受体在apoE2降低胆固醇作用中的可能作用，我们将表达低水平apoE2的转基因小鼠与LDL受体缺失小鼠(hE(2+/0)，LDLR-/-)进行交配。即使在不存在 LDL 受体的情况下，血浆总胆固醇和 LDL 胆固醇水平也会随着血浆 apoE2 水平的增加而逐渐降低。当血浆 apoE2 水平 >20 mg/dl 时，LDL 胆固醇比 LDLR-/- 小鼠低 45%。因此，apoE2 的 LDL 胆固醇降低作用不依赖于 LDL 受体。相比之下，随着apoE2水平的增加，血浆甘油三酯水平（主要是极低密度脂蛋白（VLDL）和中密度脂蛋白（IDL））逐渐增加。当血浆 apoE2 水平 >20 mg/dl 时，甘油三酯比 LDLR-/- 小鼠高出 150%。此外，在apoE缺失小鼠（hE2（+/0）、mE（-/-））中，apoE2水平也与血浆甘油三酯水平呈正相关，表明hE2（+/0）、LDLR-/-和hE2（+/0）、mE（-/-）小鼠的脂肪分解受损。与正常 VLDL 和 IDL 相比，用小鼠肝素后血浆孵育来自 hE2(+/0)、LDLR-/- 或 hE2(+/0)、mE(-/-) 小鼠的 VLDL 或 IDL 抑制脂蛋白脂肪酶介导的含 apoE2 VLDL 和 IDL 的脂肪分解，分别类似于 80% 和类似于 70%，该观察结果通过富含甘油三酯的乳液颗粒的研究得到证实， apoE2和纯化的脂蛋白脂肪酶，此外，含有apoE2的VLDL的apoC-II比正常VLDL少得多。在孵育中添加apoC-II可以部分纠正含有apoE2的VLDL或IDL中apoE2受损的脂解作用，并完全纠正含有apoE2的乳液颗粒中的脂解作用。因此，apoE2 通过损害脂蛋白脂肪酶介导的富含甘油三酯的脂蛋白的脂解作用（主要是通过置换或掩蔽 apoC-II）来降低 LDL 胆固醇。此外，apoE2 对血浆胆固醇和甘油三酯水平的影响是剂量依赖性的，并通过不同的机制起作用。 apoE2引起的血浆胆固醇升高主要是由于清除受损，而血浆甘油三酯升高主要是由于apoE2对富含甘油三酯的脂蛋白的脂解作用受损所致。
Apolipoprotein (apo) E2 is often associated with low levels of low density lipoprotein (LDL) cholesterol and high levels of plasma triglycerides in humans. Mice expressing apoE2 also have low LDL levels. To evaluate the possible role of the LDL receptor in the cholesterol-lowering effect of apoE2, we bred transgenic mice expressing low levels of apoE2 with LDL receptor-null mice (hE(2+/0),LDLR-/-). Even in the absence of the LDL receptor, plasma total and LDL cholesterol levels decreased progressively with increasing levels of plasma apoE2, At plasma apoE2 levels >20 mg/dl, LDL cholesterol was similar to 45% lower than in LDLR-/- mice. Thus, the LDL cholesterol-lowering effect of apoE2 is independent of the LDL receptor. In contrast, plasma triglyceride levels increased (mostly in very low density lipoproteins (VLDL) and intermediate density Lipoproteins (IDL)) progressively as apoE2 levels increased. At plasma apoE2 levels >20 mg/dl, triglycerides were similar to 150% higher than in LDLR-/- mice. Furthermore, in apoE-null mice (hE2(+/0), mE(-/-)), apoE2 levels also correlated positively with plasma triglyceride levels, suggesting impaired lipolysis in both hE2(+/0),LDLR-/- and hE2(+/0),mE(-/-) mice. Incubating VLDL or IDL from the hE2(+/0),LDLR-/- or the hE2(+/0),mE(-/-) mice with mouse postheparin plasma inhibited lipoprotein lipase-mediated lipolysis of apoE2-containing VLDL and IDL by similar to 80 and similar to 70%, respectively, versus normal VLDL and IDL, This observation was confirmed by studies with triglyceride-rich emulsion particles, apoE2, and purified lipoprotein lipase, Furthermore, apoE2-containing VLDL had much less apoC-II than normal VLDL. Adding apoC-II to the incubation partially corrected the apoE2-impaired lipolysis in apoE2-containing VLDL or IDL and corrected it completely in apoE2-containing emulsion particles. Thus, apoE2 lowers LDL cholesterol by impairing lipoprotein lipase mediated lipolysis of triglyceride rich lipoproteins (mostly by displacing or masking apoC-II), Furthermore, the effects of apoE2 on both plasma cholesterol and triglyceride levels are dose dependent and act via different mechanisms. The increase in plasma cholesterol caused by apoE2 is due mostly to impaired clearance, whereas the increase in plasma triglycerides is caused mainly by apoE2-impaired Lipolysis of triglyceride-rich Lipoproteins.