The intracellular transport of low density lipoprotein-derived cholesterol is inhibited in Chinese hamster ovary cells cultured with 3-β-[2-(diethylamino)ethoxy]androst-5-en-17-one

• Published in: The Journal of biological chemistry 1989-07, Vol.264 (20), p.11796-11806
• Main Authors: Liscum, L, Faust, J R
• Format: Article
• Language: English
• Subjects: Androstenes - pharmacology; Animals; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Biological Transport; Cell Line; Cell Membrane - metabolism; Cell physiology; Cholesterol, LDL - antagonists & inhibitors; Cholesterol, LDL - metabolism; Cricetinae; Cricetulus; Depression, Chemical; Fundamental and applied biological sciences. Psychology; Hydrolysis; Hydroxycholesterols - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; Membrane and intracellular transports; Molecular and cellular biology; Receptors, LDL - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)80136-3

In mammalian cells, low density lipoprotein (LDL) is bound, internalized, and delivered to lysosomes where LDL-cholesteryl esters are hydrolyzed to unesterified cholesterol. The mechanisms of intracellular transport of LDL-cholesterol from lysosomes to other cellular sites and LDL-mediated regulation of cellular cholesterol metabolism are unknown. We have identified a pharmacological agent, U18666A (3-β-[2-diethyl-amino)ethoxy]androst-5-en-17-one), which impairs the intracellular transport of LDL-derived cholesterol in cultured Chinese hamster ovary (CHO) cells. U18666A blocks the ability of LDL-derived cholesterol to stimulate cholesterol esterification, and to suppress 3-hydroxy-3-methylglutaryl-coenzyme A reductase and LDL receptor activities. However, U18666A does not impair 25-hydroxycholesterol-mediated regulation of these processes. In addition, U18666A impedes the ability of LDL-derived cholesterol to support the growth of CHO cells. However, U18666A has only moderate effects on growth supported by non-lipoprotein cholesterol. LDL binding, internalization, and lysosomal hydrolysis of LDL-cholesteryl esters are not affected by the presence of U18666A. Analysis of intracellular cholesterol transport reveals that LDL-derived cholesterol accumulates in the lysosomes of U18666A-treated CHO cells which results in impaired movement of LDL-derived cholesterol to other cell membranes.