Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers

Repa, Joyce J.; Turley, Stephen D.; Lobaccaro, Jean Marc; Medina, Julio C.; Li, L.; Lustig, Kevin D.; Shan, Bei; Heyman, Richard A.; Dietschy, John M.; Mangelsdorf, David J.

doi:10.1126/science.289.5484.1524

Cited by 1,193 publications

(1,006 citation statements)

References 41 publications

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“…The expression level of ARL7 mRNA was induced further by applying synthetic agonists specific for the nuclear receptors LXR and RXR and was repressed by cellular sterol unloading with 2-hydroxypropyl-bcyclodextrin. Such an expression pattern is similar to that observed for the cellular lipid exporters ATP-binding cassette transporter family members ABCA1 and ABCG1 [15,18]. The range of expression observed for the ARL7 transcript was a difference of 5.87 AE 0.12 cycles at threshold corresponding to a 58.5-fold (AE1.1-fold) expression difference.…”

Section: Differential Expression Analysissupporting

confidence: 51%

ADP-ribosylation factor (ARF)-like 7 (ARL7) is induced by cholesterol loading and participates in apolipoprotein AI-dependent cholesterol export

ENGEL¹

2004

FEBS Letters

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Here, we identify ADP-ribosylation factor (ARF)-like 7 (ARL7) as the only ARF-and ARL-family member whose mRNA-expression is induced by liver X-receptor/retinoid Xreceptor agonists or cholesterol loading in human macrophages. Moreover, subcellular distribution of mutant and wild type ARL7-enhanced green fluorescent protein (EGFP) supports that ARL7 may be involved in a vesicular transport step between a perinuclear compartment and the plasma membrane. Therefore, we investigated the effect of ARL7 over-expression on the cholesterol secretory pathway. We found that expression of wild type and dominant active ARL7-EGFP stimulated the rate of apolipoprotein AI-specific cholesterol efflux 1.7-and 2.8-fold. In contrast, expression of the dominant negative form of ARL7-EGFP led to $50% inhibition of cholesterol efflux. This data is consistent with a model in which ARL7 is involved in transport between a perinuclear compartment and the plasma membrane apparently linked to the ABCA1-mediated cholesterol secretion pathway.

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Section: Differential Expression Analysissupporting

confidence: 51%

ADP-ribosylation factor (ARF)-like 7 (ARL7) is induced by cholesterol loading and participates in apolipoprotein AI-dependent cholesterol export

ENGEL¹

2004

FEBS Letters

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“…Venkateswaran, et al, [24] suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors. Repa, et al, [25] identify the heterodimer of LXR/RXR on the upregulation of ABCA1 expression. The responsible control element was mapped to an imperfect direct repeat of the nuclear receptor half-site TGACCT separated by four bases (DR-4) that binds LXR/RXR heterodimers [26].…”

Section: Discussionmentioning

confidence: 99%

ABCA1 upregulating apolipoproein M expression mediates via the RXR/LXR pathway in HepG2 cells

Wang

Liu

et al. 2012

Biochemical and Biophysical Research Communications

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We have previously reported that liver X receptor (LXR) agonist, TO901317, could significantly inhibit hepatic apolipoprotein M (apoM) expression. It has been reported that TO901317 could activate the ATP-binding cassette transporter A1 (ABCA1) that mediates cholesterol efflux to the lipid-poor apoAI, which is an essential step for the high-density lipoprotein (HDL) formation. It is unknown if ABCA1 may regulate hepatic apoM expression. In the present study, HepG2 cells were cultured with the synthetic LXR agonists, TO901317 or GW3965 in the presence or absence of ABCA1 antagonist, disodium 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS). The mRNA levels of ABCA1, apoM and liver receptor homologue-1 (LRH-1) determined by the real-time RT-PCR. It demonstrated that both TO901317 and GW3965 could significantly enhance ABCA1 expression, and simultaneously, inhibit LRH1 expression. However, TO901317 alone could significantly inhibit apoM expression, while GW3965 alone did not influence apoM expression. ABCA1 antagonist, DIDS, have no effects on GW3965 induced upregulation of ABCA1 and downregulation of LRH1. However, apoM mRNA level was significantly decreased when the cells cultured with GW3965 together with DIDS. The present study demonstrated that apoM expression could be elevated by ABCA1 via the RXR/LXR pathway and LRH1 does not involve in the regulation of apoM by the activation of ABCA1, although the direct regulative pathway(s) between ABCA1 and apoM gene is still unknown yet.The detailed mechanism needs further investigation. 4Keywords: ATP-Binding cassette transporters; Apolipoprotein M; Liver Receptor Homolog-1; Liver X receptor Apolipoprotein M (apoM), one of the most recently discovered plasma apolipoproteins, is mainly associated with high density lipoproteins (HDL), with only a small proportion located in low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles [1]. Human apoM is exclusively expressed in the hepatocytes in liver and tubular epithelial cell in kidney, and small amounts were also found in fetal liver and fetal kidney [2]. Luo, et al.,[3] demonstrated that apoM could also be abundantly expressed in human colorectal tissues, although the pathophysiological importance of this expression and if it could influence plasma apoM pool are unknown. Wolfrum, et al., [4] demonstrated that apoM, by influencing preβ-HDL formation, being an important regulator of HDL metabolism in vivo, which could influence cholesterol efflux and the susceptibility of atherosclerosis. They elucidated the molecular mechanism by which apoM affects HDL particle size and to exploit a possible new pathway for therapeutic strategies aiming to reduce the development or progression of atherosclerosis [4]. ApoM mRNA levels could be regulated by many intracellular and extracellular factors, including platelet activating factor (PAF), insulin, leptin, transforming growth factor-beta (TGF-β), epidermal growth factor (EGF), hepatic growth factor (HGF), etc., although the function of apoM is un...

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“…NR1H3 regulates many target genes involved in lipid uptake and efflux and lipoprotein metabolism. 15 NR1H3 activators promote (i) the cellular transmembrane transport of endogenous lipid substrates via the induction of ABCA1, ABCG1, ABCG5, ABCG4, ABCG8 16,17 in human macrophages and intestine; 18 (ii) the cholesterol trafficking from the endosome/lysosome to the plasma membrane through the activation of Niemann-Pick C (NPC) 1 and NPC2 expression in human macrophages; 19 (iii) the regulation of acceptors in cholesterol efflux such as ApoE, ApoCI, ApoCII and ApoCIV expression in adipocytes and macrophages 20 ; and (iv) the remodeling of lipoproteins through the control of modifying enzymes such as lipoprotein lipase (LPL) 21 and PLTP in liver and macrophages. 5 To support this, it has been shown that NR1H3 agonists raise plasma HDLcholesterol and triglyceride levels.…”

Section: Discussionmentioning

confidence: 99%

Association between liver X receptor α gene polymorphisms and risk of metabolic syndrome in French populations

et al. 2008

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Context:The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor a (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome. Objective: In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility. Design: Two large French population-based studies (n ¼ 1130 and 1160) including overall 664 individuals with and 1626 individuals without metabolic syndrome were genotyped for three polymorphisms (rs12221497, rs11039155 and rs2279239) of NR1H3. Results: We found that the À6A allele of rs11039155 was consistently associated with a 30% reduction in risk of metabolic syndrome in the two independent population samples (adjusted OR (95% CI) ¼ 0.68 (0.53-0.86), P ¼ 0.001 for the combined sample). Moreover, it was associated with an increase in plasma HDL-cholesterol concentrations (P ¼ 0.02 for the combined sample). Neither rs12221497 nor rs11039155, both polymorphisms located in the 5 0 region of NR1H3, had significant influence on NR1H3 and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages. Conclusions: These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome.

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Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers

Cited by 1,193 publications

References 41 publications

ADP-ribosylation factor (ARF)-like 7 (ARL7) is induced by cholesterol loading and participates in apolipoprotein AI-dependent cholesterol export

ADP-ribosylation factor (ARF)-like 7 (ARL7) is induced by cholesterol loading and participates in apolipoprotein AI-dependent cholesterol export

ABCA1 upregulating apolipoproein M expression mediates via the RXR/LXR pathway in HepG2 cells

Association between liver X receptor α gene polymorphisms and risk of metabolic syndrome in French populations

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