A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake

• Published in: Atherosclerosis Vol. 194; no. 2; pp. 300 - 308
• Main Authors: Nishizawa, Tomohiro, Kitayama, Ken, Wakabayashi, Kenji, Yamada, Makiko, Uchiyama, Minoru, Abe, Koji, Ubukata, Naoko, Inaba, Toshimori, Oda, Tomiichiro, Amemiya, Yoshiya
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.10.2007; Elsevier
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; CD36 Antigens - drug effects; Cell Line, Transformed; Cholesterol, HDL - chemistry; Cholesterol, HDL - drug effects; Cholesterol, HDL - metabolism; Coronary heart disease; Cricetinae; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; General and cellular metabolism. Vitamins; Heart; High-density lipoprotein; Humans; Hyperlipidemia; Male; Medical sciences; Mesocricetus; Mice; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Piperazines - pharmacology; Rats; Scavenger receptor BI; Scavenger Receptors, Class B - antagonists & inhibitors; Scavenger Receptors, Class B - drug effects; Scavenger Receptors, Class B - genetics; High-density lipoprotein; Hyperlipidemia; Scavenger receptor BI; Rat; Liver; Hepatic disease; Hepatocellular carcinoma; Lipids; Cardiovascular disease; Lipoprotein a; Vascular disease; Particle; Prevention; Cholesterol HDL; Atherosclerosis; Hyperlipemia; Dyslipemia; Lipoprotein HDL; Mechanism of action; Digestive system; Rodentia; Metabolic diseases; Malignant tumor; Uptake; Vertebrata; Mammalia; Mouse; Animal; Digestive diseases; Hamster; Cancer; Tracers
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2006.10.025

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 100 mg/kg. To investigate the mechanism of action of R-138329, we examined the effect of R-138329 on the clearance of [3 H]cholesterol ether ([3 H]COE)-labeled and [125 I]-labeled HDL in mice. R-138329 delayed the clearance of [3 H]COE-labeled HDL and reduced accumulation of tracer HDL in the liver, whereas the clearance of [125 I]-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 [3 H]COE-labeled HDL in McA-RH 7777 rat hepatoma cells. Furthermore, 100 nM of R-154716 completely inhibited [3 H]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.