Hua Y, Kandadi MR, Zhu M, Ren J, Sreejayan N
Tauroursodeoxycholic Acid Attenuates Lipid Accumulation in Endoplasmic Reticulum-Stressed Macrophages. [JOURNAL ARTICLE]
J Cardiovasc Pharmacol 2009 Oct 9.
BACKGROUND/
AIM:: Recent evidence suggests that endoplasmic reticulum (ER) stress provoked under diabetic conditions augments the expression of scavenger receptors on macrophages, promoting the uptake of oxidized low-density lipoprotein (ox-LDL) uptake and atherogenesis. The aim of the present study was to test the hypothesis that the chemical chaperone tauroursodeoxycholic acid (TUDCA) attenuates lipid accumulation in macrophages subjected to ER stress.
METHODS:: Cultured human macrophages were subjected to ER-stress by treating them with tunicamycin. Lipid-uptake by macrophages subjected to ER-stress in the presence or absence of TUDCA was assessed by oil red O staining and by assessing the cellular uptake of Dil-ox-LDL by fluorescence measurement. Protein levels and phosphorylation status of ER stress markers, insulin-signalling molecules and scavenger receptor were assessed by Western blotting.
RESULTS:: Treatment of cultured human macrophages with the ER-stressor tunicamycin caused an increase in the protein levels of CD-36, and augmentation of lipid-uptake both of which were inhibited by TUDCA. TUDCA-treatment inhibited tunicamycin-induced ER-stress as evidenced by the attenuation of phosphorylation of eukaryotic translation initiation factor-2alpha and glucose reactive protein-78. In addition, TUDCA improved insulin signaling in macrophages by augmenting Akt-phosphorylation and blunting c-Jun N-terminal kinase activity.
CONCLUSION:: Inhibition of macrophage ER-stress may represent a potential strategy in preventing atherogenesis under diabetic conditions.
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