Barnard G F, Erickson S K, Cooper A D
Biochim Biophys Acta. 1986 Dec 5;879(3):301-12. doi: 10.1016/0005-2760(86)90219-5.
It has been shown previously that the rat hepatoma no. 7288C grown in vivo or in vitro expresses fewer receptors which recognize chylomicron remnants than does normal rat liver, and it was suggested that this may contribute to the deletion of dietary cholesterol-induced regulation of cholesterol synthesis in hepatomas (Barnard, G., Erickson, S. and Cooper, A. (1984) J. Clin. Invest. 74, 173-184). To investigate this further, Buffalo rats bearing hepatomas (HTC no. 7288C) were made hypercholesterolemic by feeding an atherogenic diet and hypocholesterolemic by ethinyl estradiol injections. Under all circumstances, tumor membranes had fewer receptors than liver membranes as measured by specific binding of [125I]chylomicron remnants. Ethinyl estradiol treatment increased the number of lipoprotein receptors 1.7-fold in liver membranes and 1.2-1.6-fold in tumor membranes, but hypercholesterolemia did not produce any significant changes in remnant binding to either liver or hepatoma membranes. Feeding an atherogenic diet induced a 2.4-fold increase in total cholesterol content in the liver, primarily as cholesterol ester; however, there was no change in total, free or ester cholesterol in the hepatomas. Acyl coenzyme A:cholesterol acyltransferase activity was low in this hepatoma line and neither treatment significantly affected its activity. One explanation for the lack of effect of the atherogenic diet on hepatoma cholesterol metabolism in addition to the decreased number of lipoprotein receptors might be the failure of access of lipoproteins to the tumor cell. To assess this, radioiodinated apo E-rich lipoproteins of various sizes were injected intravenously into rats with hepatomas. Their disappearance from the circulation was followed, and the uptake of each lipoprotein into a variety of tissues was determined. Chylomicron remnants were the most avidly removed particles. VLDLH, IDLH and HDLC were removed more slowly and less completely. None of the lipoproteins accumulated substantially in the tumors suggesting a limited access to the hepatoma tissue. Thus, in addition to the observed reduction in lipoprotein receptor number, limited lipoprotein access to the hepatoma tissue may be a significant factor in contributing to the apparent lack of feedback regulation of cholesterol synthesis by hepatoma tissue in vivo.
先前的研究表明，在体内或体外生长的大鼠肝癌7288C细胞所表达的识别乳糜微粒残粒的受体比正常大鼠肝脏要少，有人提出这可能是肝癌中膳食胆固醇诱导的胆固醇合成调节缺失的原因（巴纳德，G.，埃里克森，S.和库珀，A.（1984年）《临床研究杂志》74卷，173 - 184页）。为了进一步研究这一问题，给患有肝癌（HTC 7288C）的布法罗大鼠喂食致动脉粥样化饮食使其发生高胆固醇血症，通过注射乙炔雌二醇使其发生低胆固醇血症。在所有情况下，通过[125I]乳糜微粒残粒的特异性结合测定，肿瘤细胞膜上的受体比肝细胞膜上的少。乙炔雌二醇处理使肝细胞膜上的脂蛋白受体数量增加了1.7倍，肿瘤细胞膜上增加了1.2 - 1.6倍，但高胆固醇血症并未使肝或肝癌细胞膜上的残粒结合产生任何显著变化。喂食致动脉粥样化饮食使肝脏中的总胆固醇含量增加了2.4倍，主要是胆固醇酯；然而，肝癌中的总胆固醇、游离胆固醇或胆固醇酯均无变化。在这个肝癌细胞系中，酰基辅酶A：胆固醇酰基转移酶活性较低，两种处理均未对其活性产生显著影响。除了脂蛋白受体数量减少外，致动脉粥样化饮食对肝癌胆固醇代谢缺乏影响的一个解释可能是脂蛋白无法进入肿瘤细胞。为了评估这一点，将不同大小的放射性碘化富含载脂蛋白E的脂蛋白静脉注射到患有肝癌的大鼠体内。跟踪它们从循环中的消失情况，并测定每种脂蛋白在各种组织中的摄取情况。乳糜微粒残粒是最容易被清除的颗粒。极低密度脂蛋白（VLDLH）、中间密度脂蛋白（IDLH）和高密度脂蛋白胆固醇（HDLC）的清除速度较慢且不完全。没有一种脂蛋白在肿瘤中大量蓄积，这表明进入肝癌组织的机会有限。因此，除了观察到的脂蛋白受体数量减少外，脂蛋白进入肝癌组织的机会有限可能是导致肝癌组织在体内明显缺乏胆固醇合成反馈调节的一个重要因素。
