Document Detail

The endogenous regulator 24(S),25-epoxycholesterol inhibits cholesterol synthesis at DHCR24 (Seladin-1).
MedLine Citation:
PMID:  22178193     Owner:  NLM     Status:  Publisher    
The oxysterol 24(S),25-epoxycholesterol (24,25EC) can affect cholesterol metabolism at multiple points. Previously, we proposed that 24,25EC has an especially significant role in fine-tuning cholesterol synthesis, since it parallels cholesterol production, and without it, acute cholesterol synthesis is exaggerated. 24,25EC is structurally similar to desmosterol, a substrate for the enzyme 3β-hydroxysterol ∆(24)-reductase (DHCR24, also called Seladin-1) which catalyzes a final step in cholesterol synthesis. In this study, we reveal a novel mode by which 24,25EC can regulate cholesterol synthesis, by interfering with DHCR24, resulting in the rapid accumulation of the substrate desmosterol, at the expense of cholesterol. This effect was independent of DHCR24 protein levels, and was observed in multiple mammalian cell-lines, including those of hepatic and neuronal origin. Conversely, overexpression of DHCR24 blunted the inhibition by 24,25EC. We also determined that the specificity of this effect was restricted to certain side-chain oxysterols, notably those oxygenated at C-25. Importantly, endogenous levels of 24,25EC, manipulated by genetic and pharmacological methods, were sufficient to reduce DHCR24 activity. Together, our work introduces a novel role for 24,25EC in cholesterol homeostasis, through its rapid inhibition of cholesterol synthesis at DHCR24. Also, our work provides new insights into a little studied area, the post-transcriptional regulation of DHCR24, an important enzyme in human health and disease.
Eser J Zerenturk; Ika Kristiana; Saloni Gill; Andrew J Brown
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-10
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  -     ISSN:  0006-3002     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-19     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier B.V.
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