LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1

Delvecchio, Christopher J.; Bilan, Patricia; Nair, Parameswaran; Capone, John P.

doi:10.1152/ajplung.90394.2008

Cited by 41 publications

(48 citation statements)

References 48 publications

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“…As our data clearly show that the suppression of ABCG1 expression in both THP-1 and primary human macrophages, either transiently or by stable knockdown, is without effect on LXR-stimulated cholesterol efflux, then GSP2/LXR-dependent cholesterol efflux must be independent of ABCG1 expression and presumably linked to one of the plethora of other biological activities involving GPS2. In agreement with our observations, Delvecchio et al 18 recently reported that stimulation of cholesterol efflux to HDL by LXR agonists from human airway smooth muscle cells exclusively requires ABCA1 but not ABCG1. This result is in direct contrast with the situation in mouse macrophages, where deletion of ABCG1 significantly reduces cholesterol efflux from cells as we (this study and 2 ) and others have previously reported.…”

Section: Discussionsupporting

confidence: 94%

Stimulation of Cholesterol Efflux by LXR Agonists in Cholesterol-Loaded Human Macrophages Is ABCA1-Dependent but ABCG1-Independent

Larrede

Quinn

Jessup

et al. 2009

ATVB

171

118

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Objective-Maintenance of cholesterol homeostasis in human macrophages is essential to prevent foam cell formation. We evaluated the relative contribution of the ABCA1 and ABCG1 transporters to cholesterol efflux from human macrophages, and of the capacity of LXR agonists to reduce foam cell formation by stimulating export of cellular cholesterol. Methods and Results-ABCG1 mRNA levels were strongly increased in acLDL-loaded THP-1 macrophages and in HMDM on stimulation with LXR agonists. However, silencing of ABCG1 expression using ABCG1-specific siRNA indicated that ABCG1 was not essential for cholesterol efflux to HDL in cholesterol-loaded human macrophages stimulated with LXR agonists. Indeed, ABCA1 was solely responsible for the stimulation of cholesterol efflux to HDL on LXR activation, as this effect was abolished in HMDM from Tangier patients. Furthermore, depletion of cellular ATP indicated that the LXR-induced export of cholesterol was an ATP-dependent transport mechanism in human macrophages. Finally, use of an anti-Cla-1 blocking antibody identified the Cla-1 receptor as a key component in cholesterol efflux to HDL from cholesterol-loaded human macrophages. Conclusion-Our data indicate that stimulation of cholesterol efflux to HDL by LXR agonists in human foam cellsinvolves an ATP-dependent transport mechanism mediated by ABCA1 that it appears to be independent of ABCG1 expression. Key Words: ABC transporters Ⅲ LXR agonists Ⅲ cholesterol efflux Ⅲ macrophage Ⅲ foam cells I n atherosclerotic lesions, the accumulation of cellular cholesterol within macrophage "foam cells" drives lipid deposition and is a major contributor to lesion growth. It is understood that macrophages become foam cells as the result of a loss of the normal balance between cholesterol uptake (from lipoproteins) and cholesterol export. For this reason, the mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years.It is now generally accepted that HDL and its apolipoproteins are the major initial acceptors of excess cellular cholesterol. Members of the ABC transporter family have been identified as key, and potentially complementary, cellular participants in export of cholesterol to these acceptors. ABCA1 mediates cholesterol efflux most efficiently to lipidpoor apolipoprotein AI (apoAI), whereas ABCG1 promotes cholesterol export to lipidated particles such as HDL. In addition, the SR-BI receptor pathway can also promote cholesterol export to HDL particles.The contributions of ABCA1 and ABCG1 to the maintenance of macrophage cholesterol homeostasis have been most convincingly demonstrated through the effects of targeted deletion of these transporters in mice. 1 In particular, the profound effects of combined deletion of both ABCA1 and ABCG1 in mouse macrophages on their accumulation of cholesterol in vivo and on their ability to export cholesterol to either apoAI or to HDL in vitro, suggests that the combined activity of both of these transporters is essential for macrophage cholester...

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Section: Discussionsupporting

confidence: 94%

Stimulation of Cholesterol Efflux by LXR Agonists in Cholesterol-Loaded Human Macrophages Is ABCA1-Dependent but ABCG1-Independent

Larrede

Quinn

Jessup

et al. 2009

ATVB

171

118

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“…Cholesterol efflux assays were performed as previously described with minor modifications (30). Briefly, SMCs from WT and FHL2-KO mice were seeded into 24-well-plate wells at a concentration of 3 ϫ 10 5 cells per ml and allowed to adhere overnight, followed by incubation for 24 h in DMEM-F-12 plus 20% FCS plus [ 3 H]cholesterol.…”

Section: Methodsmentioning

confidence: 99%

“…The LXR-regulated gene ABCA1 is a crucial mediator of cellular cholesterol efflux in SMCs (30,31). We therefore measured both ApoAI-and HDL-mediated cholesterol efflux in WT and FHL2-KO SMCs.…”

Section: Fhl2 Interacts With Lxr␣ and Lxr␤mentioning

confidence: 99%

LIM-Only Protein FHL2 Is a Positive Regulator of Liver X Receptors in Smooth Muscle Cells Involved in Lipid Homeostasis

Kurakula

Sommer

Sokolović

et al. 2015

Molecular and Cellular Biology

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bThe LIM-only protein FHL2 is expressed in smooth muscle cells (SMCs) and inhibits SMC-rich-lesion formation. To further elucidate the role of FHL2 in SMCs, we compared the transcriptomes of SMCs derived from wild-type (WT) and FHL2 knockout (KO) mice. This revealed that in addition to the previously recognized involvement of FHL2 in SMC proliferation, the cholesterol synthesis and liver X receptor (LXR) pathways are altered in the absence of FHL2. Using coimmunoprecipitation experiments, we found that FHL2 interacts with the two LXR isoforms, LXR␣ and LXR␤. Furthermore, FHL2 strongly enhances transcriptional activity of LXR element (LXRE)-containing reporter constructs. Chromatin immunoprecipitation (ChIP) experiments on the ABCG1 promoter revealed that FHL2 enhances the association of LXR␤ with DNA. In line with these observations, we observed reduced basal transcriptional LXR activity in FHL2-KO SMCs compared to WT SMCs. This was also reflected in reduced expression of LXR target genes in intact aorta and aortic SMCs of FHL2-KO mice. Functionally, the absence of FHL2 resulted in attenuated cholesterol efflux to both ApoA-1 and high-density lipoprotein (HDL), in agreement with reduced LXR signaling. Collectively, our findings demonstrate that FHL2 is a transcriptional coactivator of LXRs and points toward FHL2 being an important determinant of cholesterol metabolism in SMCs.

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“…In agreement with LXR's ability to inhibit the immune response in macrophage cells, Delvecchio et al [82,83] have recently shown that activation of LXR in airway smooth muscle cells can also inhibit chemokines and enhance cholesterol efflux from this cell type. These findings provide a potential pathway to target inflammatory airway diseases including asthma.…”

Section: Vi) Lung and Kidneymentioning

confidence: 73%

Liver X receptors as therapeutic targets for managing cholesterol: implications for inflammatory conditions

Zhang

Chan

Cummins

2009

Clinical Lipidology

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SummaryAtherosclerosis is a disease characterized by excess cholesterol and inflammation in the blood vessels. The liver X receptors (alpha and beta) are members of the nuclear hormone receptor family that are activated by endogenous cholesterol metabolites. These receptors are widely expressed with a tissue distribution that includes the liver, intestine and macrophage. Upon activation, these receptors have been shown to increase reverse cholesterol transport from the macrophage back to the liver to aid in the removal of excess cholesterol. More recently, they have also been shown to inhibit the inflammatory response in macrophages. These functions are accomplished through direct regulation of gene transcription. Herein, we will describe the key benefits and potential risks of targeting the LXRs for the treatment of atherosclerosis.

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LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1

Cited by 41 publications

References 48 publications

Stimulation of Cholesterol Efflux by LXR Agonists in Cholesterol-Loaded Human Macrophages Is ABCA1-Dependent but ABCG1-Independent

Stimulation of Cholesterol Efflux by LXR Agonists in Cholesterol-Loaded Human Macrophages Is ABCA1-Dependent but ABCG1-Independent

LIM-Only Protein FHL2 Is a Positive Regulator of Liver X Receptors in Smooth Muscle Cells Involved in Lipid Homeostasis

Liver X receptors as therapeutic targets for managing cholesterol: implications for inflammatory conditions

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