Assessing the effects of LXR agonists on cellular cholesterol handling: a stable isotope tracer study
| Autor: | Avijit Ghosh, Robert N. Willette, Karpagam Aravindhan, Christine L. Webb, N. John DiNardo, Michael Jaye, Beat M. Jucker |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
HepG2 Benzylamines Hydrocarbons Fluorinated Gene Expression Receptors Cytoplasmic and Nuclear QD415-436 Cholesterol 7 alpha-hydroxylase Biochemistry Benzoates Models Biological Culture Media Serum-Free chemistry.chemical_compound mass isotopomer distribution analysis Endocrinology Internal medicine Cell Line Tumor medicine Humans Protein Isoforms Liver X receptor Liver X Receptors Carbon Isotopes Sulfonamides biology Cholesterol Catabolism turnover compartmental Cell Biology Orphan Nuclear Receptors DNA-Binding Proteins Kinetics chemistry ABCG1 Liver ABCA1 HMG-CoA reductase biology.protein lipids (amino acids peptides and proteins) Efflux Cholesterol Esters liver X receptor |
| Zdroj: | Journal of Lipid Research, Vol 47, Iss 6, Pp 1250-1260 (2006) |
| ISSN: | 0022-2275 |
| Popis: | The liver X receptors (LXRs) alpha and beta are responsible for the transcriptional regulation of a number of genes involved in cholesterol efflux from cells and therefore may be molecular targets 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 analyzed by mass isotopomer distribution analysis in conjunction with nonsteady state, multicompartment kinetic analysis to calculate the cholesterol fluxes. Incubation with synthetic, nonsteroidal LXR agonists (GW3965, T0901317, and SB742881) increased cholesterol synthesis (approximately 10-fold), decreased cellular cholesterol influx (71-82%), and increased cellular cholesterol efflux (1.7- to 1.9-fold) by 96 h. As a consequence of these altered cholesterol fluxes, cellular cholesterol decreased (36-39%) by 96 h. The increased cellular cholesterol turnover was associated with increased expression of the LXR-activated genes ABCA1, ABCG1, FAS, and sterol-regulatory element binding protein 1c. In summary, the mathematical model presented allows time-dependent calculations of cellular cholesterol fluxes. These data demonstrate that all of the cellular cholesterol fluxes were altered by LXR activation and that the increase in cholesterol synthesis did not compensate for the increased cellular cholesterol efflux, resulting in a net cellular cholesterol loss. |
| Databáze: | OpenAIRE |
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