Erbay E, et al., Reducing Endoplasmic Reticulum Stress through a Macrophage Lipid Chaperone Alleviates Atherosclerosis. Nat Med, 2009. 15(12): 1383-91.
Metabolon(Lipomics) results led to:
- Characterization of the mechanism of action
- Validation of potential target
- Characterization of the mechanisms underlying lipid chaperone activation to macrophage ER stress
- Reveal the lipid chaperone aP2 and steroylCoAdesaturase-1 (SCD-1) as potential targets to combat macrophage ER stress and minimize atherosclerosis
Activation of the ER stress is characteristic of lipid-laden macrophages in atherosclerotic lesions and is proposed to have a role in plaque vulnerability and acute cardiac death. It has been proposed that lipid chaperones may be a link between toxic lipids and organelle stress in macrophages. Lipidomicanalysis implicated regulation of de novo lipogenesisand desaturation, a rate-limiting step catalyzed by SCD-1, as a potential mechanism underlying chaperone driven changes in lipid composition in macrophage thus affecting lipid toxic potential. Further chaperone mediated regulation of SCD-1 activity was causally linked to lipid-induced ER stress responses in macrophage. Overall, this study shows that de novo fatty acid synthesis and desaturationcan be highly beneficial if not essential for defending ER function when macrophages are exposed to toxic lipids and it highlights how examining lipids as a class was able to identify novel targets.