Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo.
Eight proteins potentially involved in cholesterol efflux [ABCA1, ABCG1, CYP27A1, phospholipid transfer protein (PLTP), scavenger receptor type BI (SR-BI), caveolin-1, cholesteryl ester transfer protein, 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-BI (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 HDL. When HDL was used as an acceptor, overexpression of caveolin-1 or a combination of caveolin-1 and SR-BI (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 make a predominant contribution to cholesterol export from macrophages in vivo.
Mukhamedova
Nigora
N
BakerIDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.
Escher
Genevieve
G
D'Souza
Wilissa
W
Tchoua
Urbain
U
Grant
Angela
A
Krozowski
Zigmund
Z
Bukrinsky
Michael
M
Sviridov
Dmitri
D
D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology*; D001693:Biological Transport, Active / Q000502:physiology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D002784:Cholesterol