Journal
ATHEROSCLEROSIS
Volume 204, Issue 1, Pages 114-120Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2008.09.006
Keywords
Steroidogenic acute regulatory protein; Macrophage; Cholesterol; ABCG1; ABCA1; Mitochondria; Oxysterol
Funding
- National Foundation for Natural Science, PR China [30470689]
- National Institute of Health, USA [R01 HL078898]
- VA Merit Review Grant
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Hyperlipidemia is one of the most important risk factors for atherosclerosis. This can be amplified by a localized inflammatory response mediated by macrophages. Macrophages are capable of taking up excess cholesterol, and it is well known that delivery of cholesterol to the mitochondria by steroidogenic acute regulatory (StAR) protein is the rate-limiting step for cholesterol degradation in the liver. It has also been shown that overexpression of StAR in hepatocytes dramatically increases the amount of regulatory oxysterols in the nucleus, which play an important role in the maintenance of intracellular lipid homeostasis. The goal of the present study was to determine whether StAR plays a similar role in macrophages. We have found that overexpression of StAR in human THP-1 monocyte-derived macrophages decreases intracellular lipid levels, activates liver X receptor alpha (LXR alpha) and proliferation peroxysome activator receptor gamma (PPAR gamma), and increases ABCG1 and CYP27A1 expression. Furthermore, it reduces the secretion of inflammatory factors,and prevents apoptosis. These results suggest that StAR delivers cholesterol to mitochondria where regulatory oxysterols are generated. Regulatory oxysterols can in turn activate nuclear receptors, which increase expression of cholesterol efflux transporters, and decrease secretion of inflammatory factors. These effects can prevent macrophage apoptosis. These results imply a potential role of StAR in the prevention of atherosclerosis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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