ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - Reversal by a chemical chaperone

作者：Castilho Gabriela; Okuda Ligia S; Pinto Raphael S; Iborra Rodgiro T; Nakandakare Edna R; Santos Celio X; Laurindo Francisco R; Passarelli Marisa^*

来源：International Journal of Biochemistry & Cell Biology, 2012, 44(7): 1078-1086.

DOI：10.1016/j.biocel.2012.03.016

• Diabetes mellitus
• Advanced glycated albumin
• Endoplasmic reticulum stress
• ABCA-1
• Atherosclerosis
• Reverse cholesterol transport

ATP-binding cassette transporter A1 mediates the export of excess cholesterol from macrophages, contributing to the prevention of atherosclerosis. Advanced glycated albumin (AGE-alb) is prevalent in diabetes mellitus and is associated with the development of atherosclerosis. Independently of changes in ABCA-1 mRNA levels, AGE-alb induces oxidative stress and reduces ABCA-1 protein levels, which leads to macrophage lipid accumulation. These metabolic conditions are known to elicit endoplasmic reticulum (ER) stress. We sought to determine if AGE-alb induces ER stress and unfolded protein response (UPR) in macrophages and how disturbances to the ER could affect ABCA-1 content and cholesterol efflux in macrophages. AGE-alb induced a time-dependent increase in ER stress and UPR markers. ABCA-1 content and cellular cholesterol efflux were reduced by 33% and 47%, respectively, in macrophages treated with AGE-alb, and both were restored by treatment with 4-phenyl butyric acid (a chemical chaperone that alleviates ER stress), but not MG132 (a proteasome inhibitor). Tunicamycin, a classical ER stress inductor, also impaired ABCA-1 expression and cholesterol efflux (showing a decrease of 61% and 82%, respectively), confirming the deleterious effect of ER stress in macrophage cholesterol accumulation. Glycoxidation induces macrophage ER stress, which relates to the reduction in ABCA-1 and in reverse cholesterol transport, endorsing the adverse effect of macrophage ER stress in atherosclerosis. Thus, chemical chaperones that alleviate ER stress may represent a useful tool for the prevention and treatment of atherosclerosis in diabetes.

• 出版日期2012-7