Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Aorta
-
Arteriosclerosis / metabolism
-
Arteriosclerosis / pathology*
-
CCAAT-Enhancer-Binding Proteins / genetics
-
CCAAT-Enhancer-Binding Proteins / physiology*
-
Cattle
-
Caveolin 1
-
Caveolins / genetics
-
Caveolins / metabolism
-
Cell Compartmentation
-
Cell Membrane / metabolism*
-
Cell Nucleus / chemistry
-
Cells, Cultured
-
Cholesterol / metabolism*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
DNA-Binding Proteins / physiology*
-
Endoplasmic Reticulum / metabolism
-
Endothelial Cells / metabolism
-
Endothelium, Vascular / cytology*
-
Golgi Apparatus / metabolism
-
HeLa Cells / metabolism
-
Humans
-
Hydroxycholesterols / pharmacology
-
Inflammation / metabolism
-
Interleukin-8 / biosynthesis
-
Interleukin-8 / genetics
-
Intracellular Signaling Peptides and Proteins
-
Membrane Lipids / metabolism
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Phosphatidylcholines / pharmacology
-
Phospholipid Ethers / pharmacology
-
Recombinant Fusion Proteins / metabolism
-
STAT3 Transcription Factor
-
Sterol Regulatory Element Binding Protein 1
-
Sterol Regulatory Element Binding Protein 2
-
Trans-Activators / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / physiology*
-
Transcription, Genetic / drug effects
-
Transfection
-
beta-Cyclodextrins / pharmacology
Substances
-
1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine
-
CAV1 protein, human
-
CCAAT-Enhancer-Binding Proteins
-
Caveolin 1
-
Caveolins
-
DNA-Binding Proteins
-
Hydroxycholesterols
-
Interleukin-8
-
Intracellular Signaling Peptides and Proteins
-
Membrane Lipids
-
Membrane Proteins
-
Phosphatidylcholines
-
Phospholipid Ethers
-
Recombinant Fusion Proteins
-
SREBF1 protein, human
-
SREBF2 protein, human
-
SREBP cleavage-activating protein
-
STAT3 Transcription Factor
-
STAT3 protein, human
-
Sterol Regulatory Element Binding Protein 1
-
Sterol Regulatory Element Binding Protein 2
-
Trans-Activators
-
Transcription Factors
-
beta-Cyclodextrins
-
methyl-beta-cyclodextrin
-
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine
-
25-hydroxycholesterol
-
Cholesterol