J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

A more recent version of this article appeared on June 1, 2006

Papers In Press, published online ahead of print March 27, 2006
J. Lipid Res., doi:10.1194/jlr.M500512-JLR200
This Article
Right arrow Full Text (Accepted Manuscript)
Right arrow All Versions of this Article:
M500512-JLR200v1
47/6/1250    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aravindhan, K.
Right arrow Articles by Jucker, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aravindhan, K.
Right arrow Articles by Jucker, B. M.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Submitted on November 22, 2005
Revised on March 9, 2006
Accepted on March 27, 2006

Assessing the effects of LXR agonists on cellular cholesterol handling: A stable isotope tracer study

Karpagam Aravindhan, Christine L. Webb, Michael Jaye, Avijit Ghosh, Robert N. Willette, N. John DiNardo, and Beat M. Jucker

CVU CEDD Biology, GlaxoSmithKline, King of Prussia, PA 19406

Corresponding Author: beat_m_jucker{at}gsk.com

The liver X receptors a and ß (LXR) are responsible for the transcriptional regulation of a number of genes involved in cholesterol efflux from cells and therefore may be molecular target for the treatment of cardiovascular disease. However, the effects of LXR ligands on cholesterol turnover in cells has not been examined comprehensively. In this study, cellular cholesterol handling (e.g. synthesis, catabolism, influx and efflux) was examined using a stable isotope labeling study and a two-compartment modeling scheme. In HepG2 cells, the incorporation of 13C into cholesterol from 1-13C acetate was analysed by Mass Isotopomer Distribution Analysis (MIDA) in conjunction with the non-steady state, multicompartment kinetic analysis to calculate the cholesterol fluxes. Incubation with synthetic, non-steroidal LXR agonists (GW3965, T0901317 and SB742881), increased cholesterol synthesis (~10 fold) and decreased cellular cholesterol influx (71-82%) and increased cellular cholesterol efflux (1.7-1.9 fold) by 96 hours. As a consequence of these altered cholesterol fluxes, cellular cholesterol decreased (36-39%) by 96 hours. The increased cellular cholesterol turnover was associated with increased expression of LXR activated genes ABCA1, ABCG1, FAS and SREBP1c. In summary the mathematical model presented allows time dependent calculations of cellular cholesterol fluxes. These data demonstrate that all the cellular cholesterol fluxes were altered by LXR activation and the increase in cholesterol synthesis did not compensate for the increased cellular cholesterol efflux thereby resulting in a net cellular cholesterol loss.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.