scholarly journals The Role of Neutral Cholesterol Ester Hydrolysis in Macrophage Foam Cells

2011 ◽  
Vol 18 (5) ◽  
pp. 359-364 ◽  
Author(s):  
Motohiro Sekiya ◽  
Jun-ichi Osuga ◽  
Masaki Igarashi ◽  
Hiroaki Okazaki ◽  
Shun Ishibashi
Keyword(s):  
Cholesterol Ester ◽  
Foam Cells ◽  
Ester Hydrolysis ◽  
Macrophage Foam Cells

scholarly journals Epoxycholesterol Impairs Cholesteryl Ester Hydrolysis in Macrophage Foam Cells, Resulting in Decreased Cholesterol Efflux

2008 ◽  
Vol 28 (6) ◽  
pp. 1144-1150 ◽  
Author(s):  
Mireille Ouimet ◽  
Ming-Dong Wang ◽  
Natalie Cadotte ◽  
Kenneth Ho ◽  
Yves L. Marcel
Keyword(s):  
Cholesteryl Ester ◽  
Cholesterol Efflux ◽  
Foam Cells ◽  
Ester Hydrolysis ◽  
Macrophage Foam Cells

Abstract 536: Lysosome Insufficiency in Atherosclerosis Prone DBA/2 Mouse Macrophages Associated With Impaired Autolysosome Formation and Lipid Drop Clearance

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Peggy Robinet ◽  
Jonathan D Smith
Keyword(s):  
Cathepsin L ◽  
Foam Cells ◽  
Lysosomal Degradation ◽  
Over Expression ◽  
Protein Levels ◽  
Lysosome Biogenesis ◽  
Mouse Macrophages ◽  
Macrophage Foam Cells ◽  
And Function

In a previous study, we identified autolysosome formation as the limiting step for turnover of cholesterol esters in lipid droplets of macrophage foam cells from the atherosclerosis sensitive DBA/2 strain compared to the atherosclerosis resistant AKR mouse strain. As autophagosome formation was similar in these two strains, we wanted to evaluate the role of lysosome biogenesis and function on autolysosome formation in AKR and DBA/2 cells. The transcription factor TFEB is a key regulator for lysosome biogenesis and function that positively regulates the expression of lysosomal enzymes and structural proteins, and controls lysosomes number. For all our studies, we cultured AKR and DBA/2 macrophages with or without acetylated LDL (AcLDL) for 24h. First, we analyzed TFEB protein expression by western blot. Upon loading, TFEB was increased in AKR (48%, p<0.01) but not DBA/2 cells leading to a 45% higher TFEB level in AKR vs. DBA/2 foam cells (p<0.05), suggesting that lysosome number and function may be impaired in DBA/2 foam cells. To assess lysosome function and number, cells were labeled with Lysotracker red DND-99 (LyT) and analyzed by flow cytometry. We found that AcLDL loading did not affect LyT intensity. However, in both unloaded and loaded conditions, DBA/2 cells exhibited a 30 to 50% lower LyT intensity suggesting that they have intrinsically decreased lysosome number/function. Lysosomal degradation capacity was assayed by incubation with DQ-ovalbumin and we observed a 27% decrease in lysosome function in DBA/2 vs. AKR foam cells (p<0.01). In addition, upon loading, the mature form of cathepsin L was increased in AKR (43%, p<0.05) but not DBA/2 cells. Together these data suggest an impairment of lysosomal degradation capacity in DBA/2 foam cells. Finally, we investigated the role of TPC2, a lysosomal membrane protein which over expression has been previously linked to a defect in autolysosome formation. We found that upon AcLDL loading TPC2 protein levels were increased by 35% in DBA/2 cells, which are defective in autolysosome formation, while they were unchanged in AKR cells. In conclusion, we found that DBA/2 vs. AKR foam cells express more TPC2 and have fewer and/or dysfunctional lysosomes that may explain the autolysosome formation defect in these cells.

Abstract 13: Development of Functionalized Nanoparticle Platform for Reducing Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Shobha Ghosh ◽  
Jing Wang ◽  
Jinghua Bie ◽  
Quan Yuan ◽  
Olga Zolotarskaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Studies ◽  
Target Gene ◽  
Foam Cells ◽  
Expression Vectors ◽  
Transgenic Expression ◽  
Target Gene Expression ◽  
Macrophage Foam Cells ◽  
Plaque Regression

No therapy is currently available to enhance the removal of cholesteryl esters (CE) from existing atherosclerotic plaques to facilitate plaque regression. Such a strategy is crucial to reduce the burden of existing disease in addition to preventing the progression targeted by the current therapeutics. Earlier studies from our laboratory have established the anti-atherogenic role of CE hydrolase (CEH)-mediated CE mobilization from macrophage foam cells and final elimination of cholesterol by the liver. While transgenic expression of CEH was used in pre-clinical animal studies, increase in human CEH by activation of Liver-X-receptor (LXR) was also established. Increased lipogenesis induced by LXR ligands precludes their use. The current studies focused on the development of mannose-functionalized dendrimer nanoparticles (DNPs) for the delivery of LXR ligand (TO901317) or CEH expression vector to plaque associated macrophage foam cells. As shown in the Figure, mannose functionalization restricts the uptake of DNPs to macrophages and minimal uptake was seen with primary hepatocytes ( A ). Western diet fed LDLR-/- mice were injected (iv) with DNPs and tissues harvested 48 later to monitor gene expression by QPCR. DNP-mediated delivery of LXR ligand (DNP-LXR) increased the target gene expression (ABCA1, ABCG1) in plaque associated macrophage foam cells in the aortic arch with no effects on target gene expression in the liver ( B ) demonstrating the specific delivery of LXR ligand. Comparable increase in CEH activity was seen following exposure of macrophages to free LXR ligand and DNP-delivered LXR ligand ( C ) and DNP-mediated delivery of CEH expression vectors driven either by CMV or SR-A promoter induced dramatic increase in CEH expression ( D ). These data establish functionalized DNP as a suitable platform for specific and functional delivery of drugs or DNA to plaque associated macrophages to enhance processes involved in cholesterol removal and plaque regression.

scholarly journals Elimination of Cholesterol Ester from Macrophage Foam Cells by Adenovirus-mediated Gene Transfer of Hormone-sensitive Lipase

2002 ◽  
Vol 277 (35) ◽  
pp. 31893-31899 ◽  
Author(s):  
Hiroaki Okazaki ◽  
Jun-ichi Osuga ◽  
Kazuhisa Tsukamoto ◽  
Naoyuki Isoo ◽  
Tetsuya Kitamine ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cholesterol Ester ◽  
Foam Cells ◽  
Hormone Sensitive Lipase ◽  
Macrophage Foam Cells ◽  
Hormone Sensitive

scholarly journals Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells

2009 ◽  
Vol 50 (10) ◽  
pp. 2014-2026 ◽  
Author(s):  
Jody C. Ullery-Ricewick ◽  
Brian E. Cox ◽  
Evelyn E. Griffin ◽  
W. Gray Jerome
Keyword(s):  
Cholesteryl Ester ◽  
Cholesterol Ester ◽  
Foam Cells ◽  
Macrophage Foam Cells
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