Role for sterol regulatory element-binding protein in activation of endothelial cells by phospholipid oxidation products.
Oxidized phospholipids, including oxidation products of palmitoyl-arachidonyl-phosphatidyl choline (PAPC), are mediators of inflammation in endothelial cells (ECs) and known to induce several chemokines, including interleukin-8 (IL-8). In this study, we show that oxidized PAPC (OxPAPC), which accumulates in atherosclerotic lesions, paradoxically depletes endothelial cholesterol, causing caveolin-1 internalization from the plasma membrane to the endoplasmic reticulum and Golgi, and activates sterol regulatory element-binding protein (SREBP). Cholesterol loading reversed these effects. SREBP activation resulted in increased transcription of the low-density lipoprotein receptor, a target gene of SREBP. We also provide evidence that cholesterol depletion and SREBP activation are signals for OxPAPC induction of IL-8. Cholesterol depletion by methyl-beta-cyclodextrin induced IL-8 synthesis in a dose-dependent manner. Furthermore, cholesterol loading of ECs by either the cholesterol-cyclodextrin complex or caveolin-1 overexpression inhibited OxPAPC induction of IL-8. These observations suggest that changes in cholesterol level can modulate IL-8 synthesis in ECs. The OxPAPC induction of IL-8 was mediated through the increased binding of SREBP to the IL-8 promoter region, as revealed by mobility shift assays. Overexpression of either dominant-negative SREBP cleavage-activating protein or 25-hydroxycholesterol significantly suppressed the effect of OxPAPC on IL-8 transcription. A role for SREBP activation in atherosclerosis is suggested by the observation that EC nuclei showed strong SREBP staining in human atherosclerotic lesions. The current studies suggest a novel role for endothelial cholesterol depletion and subsequent SREBP activation in inflammatory processes in which phospholipid oxidation products accumulate.
Yeh
Michael
M
Department of Medicine, Geffen School of Medicine at University of California Los Angeles, USA.
Cole
Amy L
AL
Choi
Jenny
J
Liu
Yi
Y
Tulchinsky
Dmitry
D
Qiao
Jian-Hua
JH
Fishbein
Michael C
MC
Dooley
Alek N
AN
Hovnanian
Talin
T
Mouilleseaux
Kevin
K
Vora
Devendra K
DK
Yang
Wen-Pin
WP
Gargalovic
Peter
P
Kirchgessner
Todd
T
Shyy
John Y-J
JY
Berliner
Judith A
JA
D000818:Animals; D001011:Aorta; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002417:Cattle; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics / Q000378:metabolism; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010713:Phosphatidylcholines / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D047392:beta-Cyclodextrins / Q000494:pharmacology
C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; C495540:CAV1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D051242:Caveolin 1; D022461:Caveolins; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; D011993:Recombinant Fusion Proteins; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D015534:Trans-Activators; D014157:Transcription Factors; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; C007997:25-hydroxycholesterol; D002784:Cholesterol