Lipids are responsible for the atheromatous plaque formation during 
atherosclerosis by their deposition in the subendothelial intima of the aorta, 
leading to infarction. Sterol regulatory element-binding protein 2 (SREBP2), 
regulating cholesterol homeostasis, is suggested to play a pivotal role during 
the early incidence of atherosclerosis through dysregulation of lipid 
homeostasis. Here we demonstrate that oxidative stress stimulates 
SREBP2-mediated cholesterol uptake via low density lipoprotein receptor (LDLR), 
rather than cholesterol synthesis, in mouse vascular aortic smooth muscle cells 
(MOVAS) and THP-1 monocytes. The enhancement of mature form of SREBP2 (SREBP2-M) 
during oxidative stress was associated with the inhibition of AMP-activated 
protein kinase (AMPK) activation. In contrast, inhibition of either SREBP2 by 
fatostatin or LDLR by siLDLR resulted in decreased cholesterol levels during 
oxidative stress. Thereby confirming the role of SREBP2 in cholesterol 
regulation via LDLR. Metformin-mediated activation of AMPK was able to 
significantly abrogate cholesterol uptake by inhibiting SREBP2-M. Interestingly, 
although metformin administration attenuated angiotensin (Ang)-II-impaired lipid 
homeostasis in both aorta and liver tissues of ApoE-/- mice, the results 
indicate that SREBP2 through LDLR regulates lipid homeostasis in aorta but not 
in liver tissue. Taken together, AMPK activation inhibits oxidative 
stress-mediated SREBP2-dependent cholesterol uptake, and moreover, 
metformin-induced prevention of atheromatic events are in part due to its 
ability to regulate the SREBP2-LDLR axis.