IFN-γ down-regulates ABCA1 expression by inhibiting LXRα in a JAK/STAT signaling pathway-dependent manner

Hao, Xinrui; Cao, Dongli; Hu, Yan‐Wei; Li, Xiaoxu; Liu, Xiehong; Xiao, Ji; Liao, Duan‐Fang; Xiang, Jim; Tang, Chao-Ke

doi:10.1016/j.atherosclerosis.2008.07.029

Cited by 76 publications

(58 citation statements)

References 57 publications

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“…Recently, we found that eicosapentaenoic acid negatively affects both ABC-A1 activity and ABC-A1-dependent cholesterol efflux by decreasing ABC-A1 protein levels and by reducing cAMP/PKA-mediated ABC-A1 serine phosphorylation in THP-1 macrophage-derived foam cells [37] . Additionally, we also found that IFN-γ potentially decreases ABC-A1 expression and cholesterol efflux in THP-1 macrophagederived foam cells [38] . NO-1886, a novel compound that functions as an effective lipoprotein lipase (LPL) activator, inhibits atherosclerosis in high-fat/high-sucrose/high-cholesterol-fed Chinese Bama minipigs by increasing the mRNA and protein levels of ABC-A1 in the liver, retroperitoneal adipose tissue and aorta [39] .…”

Section: Transmembrane Transport System Of the Abc-a1 Complexmentioning

confidence: 74%

“…However, ABC-A1 mainly transfers cholesterol uni-directionally outside of cells using the energy provided by ATP. ABC-A1 is upregulated by PPAR/RXR, LXR/RXR, cAMP, and HDL and downregu- [38,63,104,109] . In general, there is a one-way and a two-way transmembrane transport system in almost all cells, but the components of the systems differ in different cells.…”

Section: Discussionmentioning

confidence: 99%

“…The main activators of LXR and RXR are oxidative sterols, whereas RXR is mainly activated by retinoids. Recently, we found that IFN-γ may first downregulate the expression of LXRα through the JAK/STAT1 signaling pathway and then decrease the expression of ABC-A1 in THP-1 macrophage-derived foam cells [38] . TGF-β1 upregulates the expression of ABC-A1, ABC-G1 and SR-BI via the LXRα signaling pathway in THP-1 macrophage-derived foam cells [60] .…”

Section: Rxr and Lxrmentioning

confidence: 99%

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A novel model of cholesterol efflux from lipid-loaded cells

et al. 2010

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Cholesterol efflux from lipid-loaded cells is a key athero-protective event that counteracts cholesterol uptake. The imbalance between cholesterol efflux and uptake determines the prevention or development of atherosclerosis. Many proteins and factors participate in the cholesterol efflux event. However, there are currently no systematic models of reverse cholesterol transport (RCT) that include most RCT-related factors and events. On the basis of recent research findings from other and our laboratories, we propose a novel model of one center and four systems with coupling transportation and networking regulation. This model represents a common way of cholesterol efflux; however, the systems in the model consist of different proteins/factors in different cells. In this review, we evaluate the novel model in vascular smooth muscle cells (VSMCs) and macrophages, which are the most important original cells of foam cells. This novel model consists of 1) a caveolae transport center, 2) an intracellular trafficking system of the caveolin-1 complex, 3) a transmembrane transport system of the ABC-A1 complex, 4) a transmembrane transport system of the SR-B1 complex, and 5) an extracelluar trafficking system of HDL/Apo-A1. In brief, the caveolin-1 system transports cholesterol from intracellular compartments to caveolae. Subsequently, both ABC-A1 and SR-B1 complex systems transfer cholesterol from caveolae to extracellular HDL/Apo-A1. The four systems are linked by a regulatory network. This model provides a simple and concise way to understand the dynamic process of atherosclerosis.

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Section: Transmembrane Transport System Of the Abc-a1 Complexmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Rxr and Lxrmentioning

confidence: 99%

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A novel model of cholesterol efflux from lipid-loaded cells

et al. 2010

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“…We also showed that IFN-γ may first downregulate the expression of LXRα through the 1344 www.nature.com/aps Chen SG et al Acta Pharmacologica Sinica npg JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophagederived foam cells [10] . In addition, eicosapentaenoic acid (EPA) reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through a cAMP/PKA pathway in THP-1 macrophage-derived foam cells [11] .…”

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confidence: 99%

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells

et al. 2010

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Aim: To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis. Methods: Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays. Results: Ibrolipim 5 and 50 μmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apoA-I or HDL. Moreover, it upregulated the expression of ABCA1 and ABCG1. In addition, LXRα was also upregulated by the ibrolipim treatment. In addition, LXRα small interfering RNA completely abolished the promotion effect that was induced by ibrolipim. Conclusion: Ibrolipim increased ABCA1 and ABCG1 expression and promoted cholesterol efflux, which was mediated by the LXRα signaling pathway.Keywords: ATP-binding membrane cassette transporter A-1; ATP-binding membrane cassette transporter G-1; ibrolipim; liver X receptor α; atherosclerosis; RNA interference; high density lipoprotein; apolipoprotein; cholesterol Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1343Sinica ( -1349 doi: 10.1038/aps.2010 published online 27 Sep 2010 Original Article # The first two authors contributed equally to this work. * To whom correspondence should be addressed.E-mail tchaoke@yahoo.com.cn Received 2010-04-26 Accepted 2010-08-17 (ABCG1) [4,5] .Ibrolipim is an effective lipoprotein lipase (LPL) activator [6] . It has previously been reported that ibrolipim increases lipoprotein lipase (LPL) mRNA in tissues and LPL activity in postheparin plasma, resulting in a reduction in plasma triglyceride levels and an elevation of HDL. Previous studies from our laboratory and others have also shown that increasing LPL activity in skeletal muscle results in decreased fat accumulation, and long-term administration of ibrolipim protects against the development of experimental atherosclerosis in animals [6][7][8] . However, the detailed mechanism for cholesterol transport proteins induced by ibrolipim is unclear.Recently, our laboratory revealed that the liver X receptors (LXR) synthetic agonist T0901317 promoted ABCA1 gene and protein levels in the aorta, liver, and small intestine of apoE-/-mice and significantly increased cholesterol efflux from peritoneal macrophages [9] . We also showed that IFN-γ may first downregulate the expression of LXRα through the 1344 www.nature.com/aps Chen SG et al Acta Pharmacologica Sinica npg JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophagederived foam cells [10] . In addition, eicosapentaenoic acid (EPA) reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through a cAMP/PKA pathway in THP-1 macrophage-derived foam cells [1...

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“…Oleate 23) , eicosapentaenoic acid 24) and IFN-gamma 25) reduced the level of ABCA1 and impaired ABCA1-dependent cholesterol efflux in THP-1 macrophage-derived foam cells. LXR agonist promoted ABCA1 expression in apoE KO mice 26) .…”

Section: Introductionmentioning

confidence: 99%