PUBLICATION
The important role of apolipoprotein A-II in ezetimibe driven reduction of high cholesterol diet-induced atherosclerosis
- Authors
- Yan, Y., He, F., Li, Z., Xu, R., Li, T., Su, J., Liu, X., Zhao, M., Wu, W.
- ID
- ZDB-PUB-181204-3
- Date
- 2018
- Source
- Atherosclerosis 280: 99-108 (Journal)
- Registered Authors
- Keywords
- Apolipoprotein A-II, Atherosclerosis, Ezetimibe, Zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Anticholesteremic Agents/pharmacology*
- Apolipoprotein A-II/blood*
- Atherosclerosis/metabolism*
- Cholesterol/metabolism*
- Diet, High-Fat/adverse effects
- Endothelial Cells/metabolism
- Ezetimibe/pharmacology*
- Granulocytes/metabolism
- Hep G2 Cells
- Hepatocyte Nuclear Factor 4/metabolism
- Hepatocytes
- Humans
- Hypercholesterolemia/metabolism
- Lipid Metabolism
- Lipids/chemistry
- Macrophages/metabolism
- Microscopy, Confocal
- PPAR alpha/metabolism
- THP-1 Cells
- Zebrafish
- PubMed
- 30500605 Full text @ Atherosclerosis
Citation
Yan, Y., He, F., Li, Z., Xu, R., Li, T., Su, J., Liu, X., Zhao, M., Wu, W. (2018) The important role of apolipoprotein A-II in ezetimibe driven reduction of high cholesterol diet-induced atherosclerosis. Atherosclerosis. 280:99-108.
Abstract
Background and aims It has been well established that ezetimibe blocks cholesterol absorption to prevent the negative effects of a high-fat diet in atherosclerosis. However, the exact mechanism is unknown. Here we use a transgenic zebrafish, which expresses different fluorescent proteins on either endothelial cells or granulocytes and macrophages, to explore the specific mechanism of ezetimibe and its role in reducing atherosclerosis-related hypercholesteremia.
Methods Zebrafish larvae were exposed to a control diet, high cholesterol diet (HCD) or a HCD with ezetimibe treatment. Both the control diet and high cholesterol diet were mixed with red or green fluorophore labeled cholesteryl ester to trace lipid distribution. Isobaric tags were used for relative and absolute quantification to examine protein expression profiles of zebrafish larvae in the different treatment groups. To knock down Apo A-II and investigate the role of Apo A-II in the anti-atherosclerotic function of ezetimibe, we used morpholinos to target zebrafish Apoa2 mRNA. To confirm ezetimibe regulatory role on Apo A-II expression, siRNA against HNF4, PPARα, and SREBP1 were transfected into HepG2 cells.
Results The results show that ezetimibe increased the expression of Apo A-II but failed to reduce vascular lipid accumulation and macrophage recruitment induced by the HCD diet when Apo A-II was knocked down. Finally, we found that ezetimibe increased the expression of Apo A-II through HNF4 and PPARα transcriptional factors.
Conclusions Our data indicates that ezetimibe may not only prevents atherosclerosis by inhibiting cholesterol absorption in the intestine, but also by increasing the expression of Apo A-II in hepatocytes, thereby enhancing reverse cholesterol transport and removing excess cholesterol from the periphery.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping