| Autor: |
François Briand, Morgan Tréguier, Agnès André, Didier Grillot, Marc Issandou, Khadija Ouguerram, Thierry Sulpice |
| Jazyk: |
angličtina |
| Rok vydání: |
2010 |
| Předmět: |
|
| Zdroj: |
Journal of Lipid Research, Vol 51, Iss 4, Pp 763-770 (2010) |
| Druh dokumentu: |
article |
| ISSN: |
0022-2275 |
| DOI: |
10.1194/jlr.M001552 |
| Popis: |
Liver X receptor (LXR) activation promotes reverse cholesterol transport (RCT) in rodents but has major side effects (increased triglycerides and LDL-cholesterol levels) in species expressing cholesteryl ester transfer protein (CETP). In the face of dyslipidemia, it remains unclear whether LXR activation stimulates RCT in CETP species. We therefore used a hamster model made dyslipidemic with a 0.3% cholesterol diet and treated with vehicle or LXR agonist GW3965 (30 mg/kg bid) over 10 days. To investigate RCT, radiolabeled 3H-cholesterol macrophages or 3H-cholesteryl oleate-HDL were then injected to measure plasma and feces radioactivity over 72 or 48 h, respectively. The cholesterol-enriched diet increased VLDL-triglycerides and total cholesterol levels in all lipoprotein fractions and strongly increased liver lipids. Overall, GW3965 failed to improve both dyslipidemia and liver steatosis. However, after 3H-cholesterol labeled macrophage injection, GW3965 treatment significantly increased the 3H-tracer appearance by 30% in plasma over 72 h, while fecal 3H-cholesterol excretion increased by 156% (P < 0.001). After 3H-cholesteryl oleate-HDL injection, GW3965 increased HDL-derived cholesterol fecal excretion by 64% (P < 0.01 vs. vehicle), while plasma fractional catabolic rate remained unchanged. Despite no beneficial effect on dyslipidemia, LXR activation promotes macrophage-to-feces RCT in dyslipidemic hamsters. These results emphasize the use of species with a more human-like lipoprotein metabolism for drug profiling. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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