The Involvement of Toll-like Receptors in OxLDL-Induced Foam Cell Formation and the Reversal Effect of Metformin

• Main Authors: Ying-Ting Chen, 陳胤廷
• Other Authors: Low-Tone Ho
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/44020802684411611719

碩士 === 國立陽明大學 === 生理學研究所 === 101 === Modified-low density lipoproteins (LDL), like oxidized-LDL or Glycated-LDL have been shown to associate with the risk of atherosclerotic cardiovascular disease. In addition, ox-LDL is responded to macrophage foam cell formation. Cholesterol homeostasis of macrophage is tightly regulated by scavenger receptor and ATP-binding cassette (ABC) transporters during the transformation of macrophage foam cells. Moreover, recent evidences reveal the involvement of Toll-like receptors in macrophage foam cell formation. Macrophage-derived foam cell is clarified to induce inflammation and plays a critical role in the initiation and progression of atherosclerosis. Metformin has been used over fifty years, which is used as first-line drug of choice for the treatment of type 2 diabetes. Reports indicate that Metformin ameliorates Hyperlipidemia in human and reduced vascular cell adhesion molecule expression in human endothelial cells. Although the underlying mechanisms of Metformin reducing macrophages foam cell formation are not fully understood, some researchers believe AMP-activated protein kinase, AMPK, is the candidate. In our condition, J774A.1 murine macrophage was the model we used. We induced macrophage foam cell formation by ox-LDL and determined macrophages lipid accumulation by Oil red O stating. Results gave reproducible evidence that ox-LDL increased macrophages lipid accumulation after 18 hours. Besides, TLR gene (TLR-2 and 4) and inflammatory gene (MCP-1, IL-6, and TNFwere significantly induced under the same condtion. Interestingly, TLR-4 was induced earlier than TLR-2. According to the results of ox-LDL induced macrophage in presence or absence of Metformin, we found it was Metformin that decreased ox-LDL-induced macrophage foam cell formation and inflammation. Also, Metformin had the effect of decreasing macrophage basal inflammatory gene and TLR gene in our condition. To understand the role of AMP-activated protein kinase (AMPK) in this experiment, compound C, the AMPK antagonist, was used to investigate whether the effect of Metformin on ox-LDL-induced macrophage foam cell through AMPK pathway. We found Metformin attenuated oxLDL-induced TLR-4、MCP-1and TNFα through AMPK activation However, TLR-2 and IL-6 were not regulated by AMPK activation. We tried to figure out the possible role of Metformin in ox-LDL-induced macrophage foam cell formation. After investigating the involvement AMPK in this condition, we found Metformin on foam cell formation and its function was through AMPK pathway. We believed Metformin had benefit to solve foam-cell-related physiologic problems.