Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport[S]

• Published in: Journal of lipid research Vol. 51; no. 12; pp. 3443 - 3454
• Main Authors: Niesor, Eric J., Magg, Christine, Ogawa, Naoto, Okamoto, Hiroshi, von der Mark, Elisabeth, Matile, Hugues, Schmid, Georg, Clerc, Roger G., Chaput, Evelyne, Blum-Kaelin, Denise, Huber, Walter, Thoma, Ralf, Pflieger, Philippe, Kakutani, Makoto, Takahashi, Daisuke, Dernick, Gregor, Maugeais, Cyrille
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2010; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: anacetrapib; Animals; Anticholesteremic Agents - pharmacology; apolipoproteins; Bile Acids and Salts - metabolism; Binding Sites; Biological Transport - drug effects; CETP; Cholesterol - blood; Cholesterol - metabolism; Cholesterol Ester Transfer Proteins - blood; Cholesterol Ester Transfer Proteins - metabolism; Cricetinae; dalcetrapib; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; high density lipoprotein-functionality; High-Density Lipoproteins, Pre-beta - blood; High-Density Lipoproteins, Pre-beta - metabolism; Humans; lipoproteins/metabolism; Oxazolidinones - pharmacology; Quinolines - pharmacology; Sulfhydryl Compounds - pharmacology; torcetrapib; CETP; apolipoproteins; anacetrapib; torcetrapib; lipoproteins/metabolism; bile acids and salts/metabolism; dalcetrapib; high density lipoprotein-functionality
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M008706

The mechanism by which cholesteryl ester transfer protein (CETP) activity affects HDL metabolism was investigated using agents that selectively target CETP (dalcetrapib, torcetrapib, anacetrapib). In contrast with torcetrapib and anacetrapib, dalcetrapib requires cysteine 13 to decrease CETP activity, measured as transfer of cholesteryl ester (CE) from HDL to LDL, and does not affect transfer of CE from HDL3 to HDL2. Only dalcetrapib induced a conformational change in CETP, when added to human plasma in vitro, also observed in vivo and correlated with CETP activity. CETP-induced pre-β-HDL formation in vitro in human plasma was unchanged by dalcetrapib ≤3 µM and increased at 10 µM. A dose-dependent inhibition of pre-β-HDL formation by torcetrapib and anacetrapib (0.1 to 10 µM) suggested that dalcetrapib modulates CETP activity. In hamsters injected with [3H]cholesterol-labeled autologous macrophages, and given dalcetrapib (100 mg twice daily), torcetrapib [30 mg once daily (QD)], or anacetrapib (30 mg QD), only dalcetrapib significantly increased fecal elimination of both [3H]neutral sterols and [3H]bile acids, whereas all compounds increased plasma HDL-[3H]cholesterol. These data suggest that modulation of CETP activity by dalcetrapib does not inhibit CETP-induced pre-β-HDL formation, which may be required to increase reverse cholesterol transport.