Impaired secretion of very low density lipoprotein triglycerides by apolipoprotein E deficient mouse hepatocytes
Impaired secretion of very low density lipoprotein triglycerides by apolipoprotein E deficient mouse hepatocytes
复制标题
DOI：
10.1172/jci119841
复制
发表时间：
1997-12-01
影响因子：
15.9
通讯作者：
Havekes, LM
中科院分区：
文献类型：
--
作者：
Kuipers, F;Jong, MC;Havekes, LM
[0133] 为了探索食物喂养的apo E缺陷小鼠肝脏中甘油三酯（TG)积累的机制（Kuipers, F., J.M. van Ree, M.H. Hofker, H. Welters, G. In't Veld, R.J. Vonk, H.M.G. Princen, and L.M. Havekes, 1996. Hepatology. 24:241-247)，我们调查了影响 apo E 缺陷对 VLDL 相关 TG 分泌的影响 (a) 小鼠体内，(b) 离体灌注小鼠肝脏，以及 (c) 培养的小鼠肝细胞。 (a) 与对照组相比，注射 Triton WR1339 后，apo E 缺陷小鼠体内肝脏 VLDL-TG 生成率降低了 46%。为了消除高胆固醇血症导致的肝功能非特异性变化导致 VLDL 分泌受损的可能性，在移植野生型小鼠骨髓后，还测量了载脂蛋白 E 缺陷小鼠的 VLDL-TG 生成率。骨髓移植的 ape E 缺陷小鼠（肝细胞中不表达 ape E）显示出正常的血浆胆固醇水平，但 VLDL-TG 的产生减少了 59%。 (b) 来自 apo E 缺陷小鼠的分离灌注肝脏的 VLDL-TG 产量比对照小鼠肝脏的产量低 50%。从灌流液中分离出的新生 VLDL 颗粒的脂质成分对于两组来说相似。 (c)与无血清培养基中的对照值相比，培养的猿E缺陷型肝细胞的VLDL-TG分泌量减少了23%，并且在培养基中存在油酸(0.75mM)以刺激脂肪生成的情况下减少了61%。电子显微镜评估显示，在油酸盐存在的情况下，与对照细胞相比，apo E 缺陷细胞产生的 VLDL 颗粒的平均尺寸更小（分别为 38 和 49 nm）。在短期标记研究中，apo E 缺陷细胞和对照细胞表现出由 [H-3] 甘油形成的 [H-3]TG 类似的时间依赖性积累，但在油酸不存在和存在的情况下，猿 E 缺陷细胞新合成的 VLDL 相关 [H-3]TG 的分泌分别减少了 60% 和 73%。我们得出结论，apo E 除了其作用外， 在脂蛋白清除中，在 VLDL 组装-分泌级联中具有生理功能。
To explore mechanisms underlying triglyceride (TG) accumulation in livers of chow-fed apo E-deficient mice (Kuipers, F., J.M. van Ree, M.H. Hofker, H. Welters, G. In't Veld, R.J. Vonk, H.M.G. Princen, and L.M. Havekes, 1996. Hepatology. 24:241-247), we investigated the effects of apo E deficiency on secretion of VLDL-associated TG (a) in vivo in mice, (b) in isolated perfused mouse livers, and (c) in cultured mouse hepatocytes. (a) Hepatic VLDL-TG production rate in vivo, determined after Triton WR1339 injection, was reduced by 46% in apo E-deficient mice compared with controls. To eliminate the possibility that impaired VLDL secretion is caused by aspecific changes in hepatic function due to hypercholesterolemia, VLDL-TG production rates were also measured in apo E-deficient mice after transplantation of wild-type mouse bone marrow. Bone marrow-transplanted ape E-deficient mice, which do not express ape E in hepatocytes, showed normalized plasma cholesterol levels, but VLDL-TG production was reduced by 59%. (b) VLDL-TG production by isolated perfused livers from apo E-deficient mice was 50% lower than production by livers from control mice. Lipid composition of nascent VLDL particles isolated from the perfusate was similar for both groups. (c) Mass VLDL-TG secretion by cultured ape E-deficient hepatocytes was reduced by 23% compared with control values in serum-free medium, and by 61% in the presence of oleate in medium (0.75 mM) to stimulate lipogenesis. Electron microscopic evaluation revealed a smaller average size for VLDL particles produced by apo E-deficient cells compared with control cells in the presence of oleate (38 and 49 nm, respectively). In short-term labeling studies, apo E-deficient and control cells showed a similar time-dependent accumulation of [H-3]TG formed from [H-3]glycerol, yet secretion of newly synthesized VLDL-associated [H-3]TG by ape E-deficient cells was reduced by 60 and 73% in the absence and presence of oleate, respectively, We conclude that apo E, in addition to its role in lipoprotein clearance, has a physiological function in the VLDL assembly-secretion cascade.