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Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox-LDL condition
Jiangping He1, Guangya Zhang1, Qi Pang2
1Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
Abstract:
SIRT6 is a pivotal regulator of lipid metabolism. It is also closely connected to cardiovascular diseases, which are the main cause of death in diabetic patients. We observed a decrease in the expression of SIRT6 and key autophagy effectors (ATG5, LC3B, and LAMP1) in ox-LDL-induced foam cells, a special form of lipid-laden macrophages. In these cells, SIRT6 WT but not SIRT6 H133Y overexpression markedly reduced foam cell formation, as shown by Oil Red O staining, while inducing autophagy flux, as determined by both mRFP-GFP-LC3 labeling and transmission electron microscopy. Silencing the key autophagy initiation gene ATG5, reversed the autophagy-promoting effect of SIRT6 in ox-LDL-treated THP1 cells, as evidenced by an increase in foam cells. Cholesterol efflux assays indicated that SIRT6 overexpression in foam cells promoted cholesterol efflux, increased the levels of ABCA1 and ABCG1, and reduced miR-33 levels. By transfecting miR-33 into cells overexpressing SIRT6, we observed that reduced foam cell formation and autophagy flux induction were largely reversed. These data imply that SIRT6 plays an essential role in protecting against atherosclerosis by reducing foam cell formation through an autophagy-dependent pathway.
Insights
Sirtuin 6 (SIRT6) reduces foam cell formation in atherosclerosis by enhancing autophagy and cholesterol efflux. This mechanism involves regulating miR-33 levels and is crucial for cardiovascular health in diabetic patients.
Area of Science:
- Biochemistry
- Cell Biology
- Cardiovascular Research
Background:
- Sirtuin 6 (SIRT6) is a key regulator of lipid metabolism and is linked to cardiovascular diseases, a major concern in diabetic patients.
- Foam cells, lipid-laden macrophages, are implicated in atherosclerosis development.
- Reduced expression of SIRT6 and autophagy markers (ATG5, LC3B, LAMP1) is observed in oxidized LDL-induced foam cells.
Purpose of the Study:
- To investigate the role of SIRT6 in regulating foam cell formation and its underlying mechanisms.
- To determine if SIRT6 influences autophagy and cholesterol efflux pathways in foam cells.
- To elucidate the role of microRNA-33 (miR-33) in SIRT6-mediated foam cell reduction.
Main Methods:
- Overexpression of wild-type (WT) and mutant (H133Y) SIRT6 in ox-LDL-induced foam cells.
- Oil Red O staining to quantify lipid accumulation.
- mRFP-GFP-LC3 labeling and transmission electron microscopy to assess autophagy flux.
- Cholesterol efflux assays measuring ABCA1 and ABCG1 levels.
- Gene silencing of ATG5 and transfection of miR-33.
Main Results:
- SIRT6 WT overexpression significantly reduced foam cell formation and induced autophagy flux, unlike SIRT6 H133Y.
- Silencing ATG5 reversed the protective effects of SIRT6 in ox-LDL-treated cells.
- SIRT6 promoted cholesterol efflux, increased ABCA1 and ABCG1 levels, and decreased miR-33 levels.
- miR-33 transfection partially reversed the beneficial effects of SIRT6.
Conclusions:
- SIRT6 protects against atherosclerosis by inhibiting foam cell formation via an autophagy-dependent pathway.
- The SIRT6-mediated reduction in foam cell formation involves modulation of cholesterol efflux and miR-33 levels.
- SIRT6 represents a potential therapeutic target for atherosclerosis, particularly in diabetic patients.
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