AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL.
BACKGROUND
Previous reports have suggested that advanced glycation end products (AGE) participate in the pathogenesis of diabetic macroangiopathy. However, current understanding of the mechanisms by which AGE may accelerate atherogenesis remains incomplete.


RESULTS
Microarray and reverse transcription real-time PCR analyses revealed that exposure to AGE-BSA (BSA, bovine serum albumin) reduced mRNA levels (60%) in the ATP-binding cassette transporter G1 (ABCG1) but not ABCA1 in human macrophages. AGE-BSA also reduced ABCG1 protein levels. These effects occurred mainly through the receptor for AGE (RAGE), as an anti-RAGE antibody significantly limited ABCG1 mRNA reduction. Functional studies demonstrated that exposure to AGE-BSA decreased cholesterol efflux to high-density lipoprotein (HDL) (P<0.05) but not to apolipoprotein AI, compared to BSA treatment. Although liver X receptors (LXR) augment ABCG1 expression, macrophages treated with AGE-BSA showed no reduction in LXR mRNA levels or in the binding of nuclear proteins to the LXR response element, compared with BSA.


CONCLUSIONS
Our data show that AGE-BSA can decrease cholesterol efflux from macrophages to HDL via an LXR-independent pathway. This novel mechanism may contribute to accelerated foam cell production and atherogenesis in diabetic patients.
Isoda
Kikuo
K
Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Folco
Eduardo J
EJ
Shimizu
Koichi
K
Libby
Peter
P
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology*
C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D017127:Glycation End Products, Advanced; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D002784:Cholesterol