Overexpression of mitochondrial cholesterol delivery protein, StAR, decreases intracellular lipids and inflammatory factors secretion in macrophages

Abstract

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 studywas 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 (LXRα) and proliferation peroxysome activator receptor gamma (PPARγ), 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.

Overexpression of the steroidogenic acute regulatory protein increases the expression of ATP-binding cassette transporters in microvascular endothelial cells (bEnd.3)

“…ABCG1, as well as ABCA1, plays a vital role on HDL-dependent cholesterol efflux in rat aortic ECs (Lin et al, 2009). In the present study, we have shown that StAR overexpression can increase the mRNA and protein expression levels of ABCA1 and ABCG1 in microvascular ECs, bEnd.3 cells, indicating that StAR plays an essential role in the maintenance of cholesterol homeostasis in ECs, as well as in hepatocytes and macrophages, as previously reported (Hall et al, 2005;Ning et al, 2009).…”

“…bEnd.3 cells were transfected by recombinant adenovirus encoding StAR (Ad-CMV-StAR) at a multiplicity of infection (MOI)=10 plaque-forming units (PFUs)/cell for 48 h, as previously described (Ning et al, 2009). Cells infected by control adenovirus encoding enhanced green-fluorescence protein infections (Ad-CMV-EGFP) and cells without virus addition (Con.)…”

“…Twenty micrograms of mitochondrial proteins were loaded for StAR determination. Western blot was done as previously described (Ning et al, 2009). …”

“…Overexpression of StAR in human acute monocytic leukemia cell line (THP-1)-derived macrophages decreases the cellular lipid levels by upregulating the levels of ABCG1 and liver-X receptor alpha (LXRα) (Ning et al, 2009). The role of StAR in cholesterol metabolism in ECs, however, is still not well understood.…”

The mammalian START domain protein family in lipid transport in health and disease

“…STARD1 overexpression in human THP-1-derived macrophages also decreases total lipid and cholesterol levels (Bai et al 2009, Ning et al 2009a. The LXRa-dependent target genes ABCG1, PPARg, LXRa, and CYP27A1 are increased at the mRNA and protein levels in the STARD1 overexpressing cells.…”