Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes
- 14 May 2009
- Vol. 44 (6), 477-487
- https://doi.org/10.1007/s11745-009-3305-7
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.Keywords
This publication has 115 references indexed in Scilit:
- Gender and age differences in expression of GABAA receptor subunits in rat somatosensory thalamus and cortex in an absence epilepsy modelNeurobiology of Disease, 2007
- Neuronal cell death caused by inhibition of intracellular cholesterol trafficking is caspase dependent and associated with activation of the mitochondrial apoptosis pathwayJournal of Neurochemistry, 2006
- The Wilson Disease Protein ATP7B Resides in the Late Endosomes with Rab7 and the Niemann-Pick C1 ProteinThe American Journal of Pathology, 2005
- Chronic exposure to U18666A induces apoptosis in cultured murine cortical neuronsBiochemical and Biophysical Research Communications, 2004
- Distribution and trafficking of MPR300 is normal in cells with cholesterol accumulated in late endocytic compartmentsJournal of Lipid Research, 2003
- Binding Structures and Potencies of Oxidosqualene Cyclase Inhibitors with the Homologous Squalene−Hopene CyclaseJournal of Medicinal Chemistry, 2003
- Cholesterol Modulates the Membrane Binding and Intracellular Distribution of Annexin 6Journal of Biological Chemistry, 2002
- Pharmacological inhibition of the intracellular transport of low-density lipoprotein-derived cholesterol in Chinese hamster ovary cellsBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1990
- Inhibition of the conversion of 7-dehydrocholesterol to cholesterol by AY-9944Biochemical and Biophysical Research Communications, 1964
- The hypocholesteremic effect of 3β-(β-dimethylaminoethoxy)-androst-5-en-17-one and its mechanism of actionBiochemical and Biophysical Research Communications, 1961