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Title: Lipid accumulation from defined species of low-density lipoprotein in THP-1 macrophages
Author: Kontovraki, Maria
ISNI:       0000 0001 3601 7785
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2007
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Lipid uptake by macrophages from oxidised low density lipoprotein (oxLDL) in vitro produces a characteristic feature of atherosclerosis namely; the formation of foam cells. Therefore, the present study established a model of 'foam cell' formation in THP-1 cells treated with 1 mg/ml and 2mg/ml of variable defined LDL species (native LDL; nLDL, minimally oxidized LDL; mmoxLDL, moderately oxidized LDL; modoxLDL and highly oxidized LDL; highlyoxLDL). The involvement of scavenger receptors SRs; CD36, CD68, SREC, LOX and SR-A, actinmediated endocytosis and PI3K/PKB/Akt pathway in lipid (total cholesterol; TC and triacylglycerol; TAG) incorporation from the LDL species in THP-1 macrophages was investigated. Oxidised species of LDL formed more foam cells and accumulated higher amounts of lipid compared to nLDL. Antibodies against CD36, CD68, SREC, LOX and SR-A were used to block these SRs in order to study their participation in lipid accumulation induced by all the LDL species. Accumulation of lipids induced by LDL species at Img/ml did not appear to involve the CD36 and CD68 SRs. However, CD36 and CD68 SRs were involved in TAG incorporation from 2mg/ml mmoxLDL and modoxLDL treatments, whereas accumulation of TC from modoxLDL was in part via LOX, SREC and SR-A SRs. Cytochalasin D, an actin-polymerisation inhibitor partially reversed TC and TAG uptake from mmoxLDL and modoxLDL at 2mg/ml whereas lipid accumulation induced by all species at Img/ml was inhibited. Interestingly, TAG uptake induced by 2mg/ml mmoxLDL and modoxLDL stimulated the PI3K pathway, whereas TC accumulation at 2mg/ml as well as lipid incorporation at Img/ml LDL species did not activate the PI3K pathway. All LDL species at 2mg/ml activate PKB/Akt in a PI3K-dependent manner, while LDL species at Img/ml LDL activate PKB/Akt in a PI3K-independent manner. IL-12 release was enhanced in THP-1 cells treated with the oxLDL species. Overall, the present study provides support that high concentrations of lipid accumulated by macrophages correlate with the extent of atherosclerotic disease in coronary arteries. Additionally, the results support the involvement of CD36, CD68, SREC, LOX and SR-A SRs, actin-dependent endocytosis and PI3K pathway, in lipid accumulation induced by all nLDL and oxLDL species in THP-1 macrophages. The present model of 'foam cell' formation can be used to further investigate diabetic and obese atherosclerotic conditions as well as atherosclerosis regression from an in vitro model that resembles in vivo conditions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available