Quantitative analysis of hydrophobic amine inhibition of intracellular cholesterol transport.

K W Underwood,B Andemariam,G L Mcwilliams,L Liscum

doi:10.1016/s0022-2275(20)39138-0

K W Underwood, B Andemariam + Show 2 more

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https://doi.org/10.1016/s0022-2275(20)39138-0

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Journal: Journal of lipid research	Publication Date: Jan 1, 1996
Citations: 85	License type: cc-by

Affiliation: Tufts University

Abstract

U18666A and imipramine are hydrophobic amines that inhibit intracellular cholesterol transport pathways. In this study, we conducted dose-response curves for each of the cholesterol transport pathways. Our analyses indicate that hydrophobic amine inhibition of LDL-stimulated cholesterol esterification is much more sensitive to inhibition than either the combined bulk movement of cholesterol from lysosomes to the plasma membrane and from the plasma membrane to the endoplasmic reticulum. Hydrophobic amines must inhibit a previously uncharacterized pathway from lysosomes to the endoplasmic reticulum or a signaling event that activates acyl CoA:cholesterol acyltransferase. Possible mechanisms for U18666A action were evaluated. The function of p-glycoprotein, which has been implicated in cholesterol transport, was unaffected by U18666A. We have evidence for a specific membrane U18666A binding site, which we hypothesize is involved in the plasma membrane to endoplasmic reticulum cholesterol transport pathway. Identification of the binding site and mechanism of hydrophobic amine action may provide information essential for understanding intracellular cholesterol transport.

Highlights

U 18666A and imipramine are hydrophobic amines that inhibit intracellular cholesterol transport pathways
Our studies indicated that U18666A abolishes low density lipoprotein (LDL)-mediated stimulation of cholesterol esterification and suppression of LDL receptor activity in Chinese hamster ovary (CHO) cells, which we attributed to impaired movement of LDL-cholesterol out of the lysosome [16].In addition to inhibiting the iysosome-to-plasma membrane pathway, U18666A inhibits cholesterol transport from the plasma membrane to the endoplasmic reticulum and mitochondria [17]
One hypothesis is that U 18666A blocks LDL stimulation of cholesterol esterification by blocking LDL-cholesterol transport pathways, for example, from lysosomes to the plasma membrane and from the plasma membrane to the endoplasmic reticulum

Summary

Introduction

U 18666A and imipramine are hydrophobic amines that inhibit intracellular cholesterol transport pathways. Our analyses indicate that hydrophobic amine inhibition of LDL-stimulated cholesterol esterificationis much more sensitive to inhibition than either the combined bulk movement of cholesterol from lysosomes to the plasma membrane and from the plasma membrane to the endoplasmic reticulum. Hydrophobic amines must inhibit a previously uncharacterized pathway from lysosomes to the endoplasmic reticulum or a signaling event that activates acyl CoA:cholesterolacyltransferase.Possible mechanisms for U18666A action were evaluated. MWe have evidence for a specific membrane U18666A binding site, which we hypothesize is involved in the plasma membrane to endoplasmic reticulum cholesterol transport pathway. Identification of the binding site and mechanism of hydrophobic amine action may provide information essential for understanding intracellular cholesterol transport.-Underwood, K. Quantitative analysis of hydrophobic amine inhibition of intracellular cholesterol transport.

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