Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo

Nigora Mukhamedova, Genevieve Escher, Wilissa D'Souza, Urbain Tchoua, Angela Grant, Zigmund Krozowski, Michael Bukrinsky, and Dmitri Sviridov

Vascular Biology, BakerIDI Heart & Diabetes Institute, Melbourne, Vic 8008

Corresponding Author: Dmitri.Sviridov{at}Bakeridi.edu.au

Eight proteins potentially involved in cholesterol efflux (ABCA1, ABCG1, CYP27A1, phospholipid transfer protein (PLTP), SR-B1, caveolin-1, cholesteryl ester transfer protein (CETP) and apolipoprotein A-I (apoA-I)) were overexpressed alone or in combination in RAW 264.7 macrophages. When apoA-I was used as an acceptor, overexpression of the combination of ABCA1, CYP27A1, PLTP and SR-B1 (Combination I) enhanced the efflux by 4.3-fold. It was established that the stimulation of efflux was due to increased abundance of ABCA1 and increased apoA-I binding to non-ABCA1 sites on macrophages. This combination caused only a small increase of the efflux to isolated high density lipoprotein (HDL). When HDL was used as an acceptor, overexpression of caveolin-1 or a combination of caveolin-1 and SR-B1 (Combination II) was the most active, doubling the efflux to HDL, without affecting the efflux to apoA-I. When tested in the in vivo mouse model of cholesterol efflux, overexpression of ABCA1 and Combination I elevated cholesterol export from macrophages to plasma, liver and feces, whereas overexpression of caveolin-1 or Combination II did not have an effect. We conclude that pathways of cholesterol efflux using apoA-I as an acceptor have a predominant contribution to cholesterol export from macrophages in vivo.

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