Tauroursodeoxycholic acid attenuates lipid accumulation in endoplasmic reticulum-stressed macrophages.
OBJECTIVE
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 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-oxidized low-density lipoprotein by fluorescence measurement. Protein levels and phosphorylation status of ER stress markers, insulin-signaling 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 cluster of differentiation 36 (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-2a 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.


CONCLUSIONS
Inhibition of macrophage ER stress may represent a potential strategy in preventing atherogenesis under diabetic conditions.
Hua
Yinan
Y
School of Pharmacy, Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, USA.
Kandadi
Machender R
MR
Zhu
Meijun
M
Ren
Jun
J
Sreejayan
Nair
N
D015153:Blotting, Western; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014415:Tunicamycin / Q000494:pharmacology
D018955:CD36 Antigens; D007328:Insulin; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D014415:Tunicamycin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine