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Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes

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  • Published:
Lipids

Abstract

The multiple actions of U18666A have enabled major discoveries in lipid research and contributed to understanding the pathophysiology of multiple diseases. This review describes these advances and the utility of U18666A as a tool in lipid research. Harry Rudney’s recognition that U18666A inhibited oxidosqualene cyclase led him to discover a pathway for formation of polar sterols that he proved to be important regulators of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. Laura Liscum’s recognition that U18666A inhibited the egress of cholesterol from late endosomes and lysosomes led to greatly improved perspective on the major pathways of intracellular cholesterol trafficking. The inhibition of cholesterol trafficking by U18666A mimicked the loss of functional Niemann–Pick type C protein responsible for NPC disease and thus provided a model for this disorder. U18666A subsequently became a tool for assessing the importance of molecular trafficking through the lysosomal pathway in other conditions such as atherosclerosis, Alzheimer’s disease, and prion infections. U18666A also provided animal models for two important disorders: petite mal (absence) epilepsy and cataracts. This was the first chronic model of absence epilepsy. U18666A is also being used to address the role of oxidative stress in apoptosis. How can one molecule have so many effects? Perhaps because of its structure as an amphipathic cationic amine it can interact and inhibit diverse proteins. Restricting the availability of cholesterol for membrane formation through inhibition of cholesterol synthesis and intracellular trafficking could also be a mechanism for broadly affecting many processes. Another possibility is that through intercalation into membrane U18666A can alter membrane order and therefore the function of resident proteins. The similarity of the effects of natural and enantiomeric U18666A on cells and the capacity of intercalated U18666A to increase membrane order are arguments in favor of this possibility.

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Abbreviations

ACAT:

Acyl cholesterol acyl transferase

APP:

β-Amyloid precursor protein

AY-9944:

trans 1, 4-bis(2-Chlorobenzylaminoethyl)cyclohexane

CHO:

Chinese hamster ovary

DHCR24:

7-Dehydrocholesterol reductase 24

DRM:

Detergent-resistant membranes

EEG:

Electroencephalogram

ER:

Endoplasmic reticulum

GABA:

Gamma aminobutyric acid

HMGCoA:

3-Hydroxy-3-methyl-glutaryl coenzyme A

LDL:

Low density lipoproteins

Mer 29 (triparanol):

(1-[p-(β-Diethylaminoethoxy)-phenyl]-1-(p-tolyl)-2-(p-chlorophenyl) ethanol

MVB:

Multivesicular bodies

NPC:

Niemann–Pick type C disease

PM:

Plasma membrane

OSC:

2, 3-Oxidosqualene cyclase

SDO:

Squalene 2, 3:22,23-dioxide

SO:

Squalene oxide

U18666A:

3-β-[2-(Diethylamino)ethoxy]androst-5-en-17-one

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Acknowledgments

This work was supported by USPHS NIH grant EY02568-29. The author remembers Harry Rudney for his encouragement and George Bierkamper for his great ideas and friendship.

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  1. Department of Biochemistry, A.T. Still University of Health Sciences, 800 West Jefferson Street, Kirksville, MO, 63501, USA

    Richard J. Cenedella

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Correspondence to Richard J. Cenedella.

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Cenedella, R.J. Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes. Lipids 44, 477–487 (2009). https://doi.org/10.1007/s11745-009-3305-7

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  • DOI: https://doi.org/10.1007/s11745-009-3305-7

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