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468 ENDOPLASMIC RETICULUM STRESS CAN CAUSE LIPID ACCUMULATION THROUGH THE ACTIVATION OF STEROL REGULATORY ELEMENT BINDING PROTEINS SM Colgan, S Lhotak, GH Werstuck, D Tang, RC Austin BACKGROUND: Sterol regulatory element binding proteins (SREBPs) are membrane bound transcription factors that upon proteolytic processing can activate the expression of genes involved in cholesterol biosynthesis and uptake. We and others have demonstrated that the accumulation of misfolded proteins within the ER, a condition known as ER stress, can dysregulate lipid metabolism by activating SREBPs. The purpose of this study is to determine the mechanism by which ER stress induces SREBP activity. We hypothesize that the proteolytic cleavage of SREBP during ER stress conditions may account for the uncontrolled production and uptake of lipids within the atherosclerotic plaque.
Hamilton, Ontario
METHODS AND RESULTS: Immunohistochemical analysis of atherosclerotic plaques from apoE deficient mice showed increased ER stress and SREBP activation. To determine the effect of ER stress on SREBP cleavage and subsequent cholesterol accumulation, Hela and THP-1 macrophages were treated with the ER stress inducing agent thapsigargin (Tg). Hela and THP-1 cells treated with Tg exhibit proteolytic cleavage of SREBP and this could be blocked with the addition of the site-1 protease inhibitor AEBSF. This suggests that Tg induced SREBP cleavage occurs through the conventional site-1/-2 pathway. Treatment of Hela or THP-1 cells with Tg also led to the accumulation of lipid observed by filipin and oil-red-o staining. Preliminary findings suggest that SREBP activation is occurring due to a loss of protein translation. Tg induced ER stress in Hela cells causes a decrease in protein synthesis through the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2
CONCLUSIONS: These results imply that during ER stress caused by Tg, SREBP is proteolytically processed by the site-1/-2 protease system that normally cleaves the SREBPs during sterol starvation. Our preliminary findings suggest that a loss in translation due to ER stress-induced eIF2a phosphorylation causes an increase in SREBP cleavage. The ability of ER stress to activate SREBP may contribute to macrophage foam cell formation and the emergence of a lipid rich necrotic core that is characteristic of advanced atherosclerotic lesions.
DNC
Heart and Stroke Foundation of Canada
Canadian Institutes of Health Research