Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis.
METHODS
Curcumin, a potent antioxidant extracted from Curcuma longa, confers protection against atherosclerosis, yet the detailed mechanisms are not fully understood. In this study, we examined the effect of curcumin on lipid accumulation and the underlying molecular mechanisms in macrophages and apolipoprotein E-deficient (apoE⁻/⁻) mice.


RESULTS
Treatment with curcumin markedly ameliorated oxidized low-density lipoprotein (oxLDL)-induced cholesterol accumulation in macrophages, which was due to decreased oxLDL uptake and increased cholesterol efflux. In addition, curcumin decreased the protein expression of scavenger receptor class A (SR-A) but increased that of ATP-binding cassette transporter (ABC) A1 and had no effect on the protein expression of CD36, class B receptor type I (SR-BI), or ATP-binding cassette transporter G1 (ABCG1). The downregulation of SR-A by curcumin was via ubiquitin-proteasome-calpain-mediated proteolysis. Furthermore, the curcumin-induced upregulation of ABCA1 was mainly through calmodulin-liver X receptor α (LXRα)-dependent transcriptional regulation. Curcumin administration modulated the expression of SR-A, ABCA1, ABCG1, and SR-BI in aortas and retarded atherosclerosis in apoE⁻/⁻ mice.


CONCLUSIONS
Our findings suggest that inhibition of SR-A-mediated oxLDL uptake and promotion of ABCA1-dependent cholesterol efflux are two crucial events in suppression of cholesterol accumulation by curcumin in the transformation of macrophage foam cells.
Department of Physiology, National Yang-Ming University, Taipei, Taiwan.
Jing-Feng
JF
Zhao
Li-Chieh
LC
Ching
Yu-Chu
YC
Huang
Chien-Yu
CY
Chen
An-Na
AN
Chiang
Yu Ru
YR
Kou
Song-Kun
SK
Shyue
Tzong-Shyuan
TS
Lee
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008817:Mice, Mutant Strains; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002147:Calmodulin; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D002154:Calpain; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin