PUBLICATION
Oxidized cholesteryl esters and phospholipids in zebrafish larvae fed a high cholesterol diet: macrophage binding and activation.
- Authors
- Fang, L., Harkewicz, R., Hartvigsen, K., Wiesner, P., Choi, S.H., Almazan, F., Pattison, J., Deer, E., Sayaphupha, T., Dennis, E.A., Witztum, J.L., Tsimikas, S., and Miller, Y.I.
- ID
- ZDB-PUB-100820-14
- Date
- 2010
- Source
- The Journal of biological chemistry 285(42): 32343-32351 (Journal)
- Registered Authors
- Miller, Yury
- Keywords
- Cholesterol, Lipid, Macrophage, Mass spectrometry (MS), Zebra fish, cholesteryl ester, oxidized, phospholipid
- MeSH Terms
-
- Animals
- Cell Line
- Cholesterol Esters/chemistry
- Cholesterol Esters/metabolism*
- Cholesterol, Dietary/metabolism*
- Diet
- Humans
- Larva/metabolism*
- Macrophages/cytology
- Macrophages/metabolism*
- Mice
- Oxidation-Reduction
- Phospholipids/chemistry
- Phospholipids/metabolism*
- Zebrafish*
- PubMed
- 20710028 Full text @ J. Biol. Chem.
Citation
Fang, L., Harkewicz, R., Hartvigsen, K., Wiesner, P., Choi, S.H., Almazan, F., Pattison, J., Deer, E., Sayaphupha, T., Dennis, E.A., Witztum, J.L., Tsimikas, S., and Miller, Y.I. (2010) Oxidized cholesteryl esters and phospholipids in zebrafish larvae fed a high cholesterol diet: macrophage binding and activation.. The Journal of biological chemistry. 285(42):32343-32351.
Abstract
A novel hypercholesterolemic zebrafish model has been developed to study early events of atherogenesis. This model utilizes optically transparent zebrafish larvae, fed a high-cholesterol diet (HCD), to monitor processes of vascular inflammation in live animals. Because lipoprotein oxidation is an important factor in the development of atherosclerosis, in this study, we characterized the oxidized lipid milieu in HCD-fed zebrafish larvae. Using liquid chromatography-mass spectrometry, we show that feeding a HCD for only 2 weeks resulted in up to 70-fold increases in specific oxidized cholesteryl esters, identical to those present in human minimally oxidized LDL (mmLDL) and in murine atherosclerotic lesions. The levels of oxidized phospholipids, such as 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine, and of various lysophosphatidylcholines were also significantly elevated. Moreover, lipoproteins isolated from homogenates of HCD-fed larvae induced cell spreading as well as ERK1/2, Akt and JNK phosphorylation in murine macrophages. Removal of apoB-containing lipoproteins from the zebrafish homogenates with an anti-human LDL antibody, as well as reducing lipid hydroperoxides with ebselen, resulted in inhibition of macrophage activation. The TLR4 deficiency in murine macrophages prevented their activation with zebrafish lipoproteins. Using biotinylated homogenates of HCD-fed larvae, we demonstrated that their components bound to murine macrophages, and this binding was effectively competed by mmLDL, but not by native LDL. These data provide evidence that molecular lipid determinants of pro-atherogenic macrophage phenotypes are present in large quantities in hypercholesterolemic zebrafish larvae and support the use of the HCD-fed zebrafish as a valuable model to study early events of atherogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping