Glucose metabolism is required for oxidized LDL-induced macrophage survival: role of PI3K and Bcl-2 family proteins.
OBJECTIVE
Oxidized low-density lipoprotein (oxLDL) induces survival of colony stimulating factor-1 (CSF-1)-dependent macrophages in vitro. Because atherosclerotic lesion-associated macrophages take up large amounts of glucose, we investigated whether, and how, oxLDL promotes glucose uptake and how glucose metabolism regulates oxLDL-induced macrophage survival.


RESULTS
OxLDL-induced macrophage survival required glucose metabolism. OxLDL stimulated 2 phases of glucose uptake, namely acute and chronic, which required PI3K but not MEK1/2 activity. PI3K appeared to regulate glucose transport via glucose transporter affinity and/or mobilization. OxLDL also maintained levels of the prosurvival proteins, Bcl-2 and Bcl-x(L), after CSF-1 had been removed through a combination of mechanisms including transcription, translation, and protein stabilization. Significantly, inhibition of glucose metabolism reduced Bcl-2 and Bcl-x(L) protein levels. MEK1/2 and PI3K activities were also required for oxLDL-induced Bcl-2 and Bcl-x(L) mRNA upregulation.


CONCLUSIONS
These results suggest that oxLDL enhances macrophage survival in the absence of CSF-1 by inducing PI3K-dependent glucose uptake, which is metabolized to maintain Bcl-2 and Bcl-x(L) protein levels.
Elsegood
Caryn L
CL
Arthritis and Inflammation Research Centre and Cooperative Research Centre for Chronic Inflammatory Diseases, Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville, Australia.
Chang
Margaret
M
Jessup
Wendy
W
Scholz
Glen M
GM
Hamilton
John A
JA
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D008077:Lipoproteins, LDL; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; C099252:oxidized low density lipoprotein; D016173:Macrophage Colony-Stimulating Factor; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D005947:Glucose