Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2894424 | Atherosclerosis | 2007 | 9 Pages |
Abstract
High-density lipoprotein (HDL) has a protective effect against atherosclerosis. Therefore, a compound that elevates the plasma HDL cholesterol (HDL-C) levels is expected to be a promising anti-atherosclerotic agent. We discovered a novel compound, R-138329, that increased HDL-C by 41% in normolipidemic hamsters at a dose of 100Â mg/kg. To investigate the mechanism of action of R-138329, we examined the effect of R-138329 on the clearance of [3H]cholesterol ether ([3H]COE)-labeled and [125I]-labeled HDL in mice. R-138329 delayed the clearance of [3H]COE-labeled HDL and reduced accumulation of tracer HDL in the liver, whereas the clearance of [125I]-labeled HDL particles was unaffected by the compound. In vitro analysis showed that R-154716, a metabolite of R-138329, dramatically inhibited the uptake of [3H]COE-labeled HDL in McA-RH 7777 rat hepatoma cells. Furthermore, 100Â nM of R-154716 completely inhibited [3H]COE-labeled HDL uptake induced by overexpression of scavenger receptor BI (SR-BI) in HEK293 cells. Taken together, these findings suggest that the mechanism by which R-138329 elevates HDL-C in vivo is principally involved in the inhibition of SR-BI-mediated selective lipid uptake in the liver.
Related Topics
Health Sciences
Medicine and Dentistry
Cardiology and Cardiovascular Medicine
Authors
Tomohiro Nishizawa, Ken Kitayama, Kenji Wakabayashi, Makiko Yamada, Minoru Uchiyama, Koji Abe, Naoko Ubukata, Toshimori Inaba, Tomiichiro Oda, Yoshiya Amemiya,