A Novel Compound Inhibits Reconstituted High-Density Lipoprotein Assembly and Blocks Nascent High-Density Lipoprotein Biogenesis Downstream of Apolipoprotein AI Binding to ATP-Binding Cassette Transporter A1-Expressing Cells

作者：Lyssenko Nicholas N; Brubaker Gregory; Smith Bradley D; Smith Jonathan D^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(11): 2700-U879.

DOI：10.1161/ATVBAHA.111.234906

• ABCA1
• apoAI
• nascent HDL
• rHDL
• reverse cholesterol transport

Objective-Nascent high-density lipoprotein (HDL) particles form from cellular lipids and extracellular lipid-free apolipoprotein AI (apoAI) in a process mediated by ATP-binding cassette transporter A1 (ABCA1). We have sought out compounds that inhibit nascent HDL biogenesis without affecting ABCA1 activity.
Methods and Results-Reconstituted HDL (rHDL) formation and cellular cholesterol efflux assays were used to show that 2 compounds that bond via hydrogen with phospholipids inhibit rHDL and nascent HDL production. In rHDL formation assays, the inhibitory effect of compound 1 (methyl 3 alpha-acetoxy-7 alpha,12 alpha-di[(phenylaminocarbonyl)amino]-5 beta-cholan-24-oate), the more active of the 2, depended on its ability to associate with phospholipids. In cell assays, compound 1 suppressed ABCA1-mediated cholesterol efflux to apoAI, the 18A peptide, and taurocholate with high specificity, without affecting ABCA1-independent cellular cholesterol efflux to HDL and endocytosis of acetylated low-density lipoprotein and transferrin. Furthermore, compound 1 did not affect ABCA1 activity adversely, as ABCA1-mediated shedding of microparticles proceeded unabated and apoAI binding to ABCA1-expressing cells increased in its presence.
Conclusion-The inhibitory effects of compound 1 support a 3-step model of nascent HDL biogenesis: plasma membrane remodeling by ABCA1, apoAI binding to ABCA1, and lipoprotein particle assembly. The compound inhibits the final step, causing accumulation of apoAI in ABCA1-expressing cells. (Arterioscler Thromb Vasc Biol. 2011;31:2700-2706.)

• 出版日期2011-11