Inhibition of notch enhances the anti-atherosclerotic effects of LXR agonists while reducing fatty liver development in ApoE-deficient mice

Abstract

Liver X receptor (LXR) activation can achieve satisfactory anti-atherosclerotic activity, but can also lead to the development of fatty liver and hypertriglyceridemia. In contrast, Notch inhibition can suppress both atherosclerosis and the hepatic accumulation of lipids. In the present study, we sought to assess whether combining LXR ligand agonists (T317) with Notch receptor inhibitors (DAPT) would lead to enhanced anti-atherosclerotic activity while overcoming the adverse events associated with LXR ligand agonist therapy. The impact of the combined T317 + DAPT therapeutic regimen on atherosclerosis, fatty liver development, and hypertriglyceridemia was assessed using ApoE deficient (ApoE−/−) mice. The results of this analysis suggested that DAPT was able to improve the anti-atherosclerotic activity of T317 without reducing the stability of lesion plaques while simultaneously reducing blood lipids in treated ApoE−/− mice. This combination T317 + DAPT treatment was also linked with a significant upregulation of ABCA1 and the stimulation of reverse cholesterol transport (RCT), as well as with decreases in the levels of intercellular cell adhesion molecule-1 (ICAM-1) and p-p65, and with altered M1/M2 macrophage proportions within atherosclerotic plaques. Importantly, DAPT was also able to reduce T317-mediated lipid accumulation within the liver owing to its ability to reduce SREBP-1 expression while simultaneously increasing that of Pi-AMPKα and PPARα. Together, our results suggest that administering Notch receptor inhibitors to ApoE−/− mice may be an effective means of enhancing the anti-atherosclerotic activity of LXR ligand agonists while simultaneously limiting associated fatty liver and hypertriglyceridemia development in these animals.