Erickson S K, Cooper A D, Barnard G F, Havel C M, Watson J A, Feingold K R, Moser A H, Hughes-Fulford M, Siperstein M D
Department of Medicine, Stanford University School of Medicine, CA.
Biochim Biophys Acta. 1988 May 22;960(2):131-8. doi: 10.1016/0005-2760(88)90058-6.
Cholesterol metabolism and its regulation are altered in hepatomas as compared to normal liver. We investigated parameters of cholesterol metabolism and their regulation in rats bearing the well-differentiated Morris hepatoma 9108. The numbers of membrane associated receptors recognizing chylomicron remnants, the lipoproteins that deliver dietary lipid to the liver, were substantially decreased in the 9108 tumor relative to the host liver. Cholesterol synthetic rates were 2-3-fold higher in the tumor, while the activity of 3-hydroxy-3-methylglutarylcoenzyme A reductase (EC 1.1.1.88), a rate-limiting enzyme for sterol synthesis, was elevated 6-14-fold. Although tumor free and esterified cholesterol contents were elevated, the activity of acylcoenzyme A:cholesterol acyltransferase (EC 2.3.1.26), the enzyme responsible for intracellular sterol esterification, was unchanged. Similar to the host liver, cholesterol synthesis and 3-hydroxy-3-methylglutarylcoenzyme A reductase were inhibited in the tumor when rats were fed a diet containing cholesterol, cholate and lard, and there was no effect on the numbers of chylomicron remnant receptors. Administering an intravenous bolus of very low density lipoproteins obtained from hypercholesterolemic rats caused an inhibition of tumor reductase activity, but had little effect on cholesterol content or cholesterol esterification. Thus, hepatoma 9108 expressed quantitative differences in cellular parameters involved in the uptake, metabolism, and synthesis of cholesterol and their susceptibility to regulation when compared with the host liver. These differences are best explained by changes in the hepatoma of multiple factors involved in the regulation of normal hepatic cholesterol metabolism.
与正常肝脏相比，肝癌中胆固醇代谢及其调节发生了改变。我们研究了患有高分化Morris肝癌9108的大鼠的胆固醇代谢参数及其调节。识别乳糜微粒残粒（将膳食脂质输送到肝脏的脂蛋白）的膜相关受体数量在9108肿瘤中相对于宿主肝脏大幅减少。肿瘤中的胆固醇合成速率高2至3倍，而3-羟基-3-甲基戊二酰辅酶A还原酶（EC 1.1.1.88，固醇合成的限速酶）的活性升高了6至14倍。尽管游离胆固醇和酯化胆固醇含量升高，但负责细胞内固醇酯化的酰基辅酶A：胆固醇酰基转移酶（EC 2.3.1.26）的活性未改变。与宿主肝脏相似，当给大鼠喂食含胆固醇、胆酸盐和猪油的饮食时，肿瘤中的胆固醇合成和3-羟基-3-甲基戊二酰辅酶A还原酶受到抑制，且对乳糜微粒残粒受体数量没有影响。静脉推注从高胆固醇血症大鼠获得的极低密度脂蛋白会抑制肿瘤还原酶活性，但对胆固醇含量或胆固醇酯化影响很小。因此，与宿主肝脏相比，肝癌9108在参与胆固醇摄取、代谢和合成的细胞参数及其调节敏感性方面表现出数量差异。这些差异最好用正常肝脏胆固醇代谢调节中涉及的多种因素在肝癌中的变化来解释。
