Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Whitney, Karl; Watson, Michael A.; Goodwin, Bryan; Galardi, Cristin M.; Maglich, Jodi M.; Wilson, Joan G.; Willson, Timothy M.; Collins, Jon L.; Kliewer, Steven A.

doi:10.1074/jbc.m106155200

Cited by 146 publications

(121 citation statements)

References 40 publications

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“…In the brain LXR␤ levels are 2-5-fold higher than in the liver, whereas LXR␣ levels are 3.5-14-fold lower than in the liver (62)(63)(64). However, 24(S)-hydroxycholesterol and GW683965A up-regulated LXR␣ but not LXR␤ expression in astrocytoma cells (data not shown), similar to what has been reported for macrophages and adipocytes, but not liver and muscle (65,66). These results suggest the possibility that the autoregulation of LXR␣ that has been suggested to occur in adipocytes to coordinate expression of target genes such as APOE (66) may also occur in brain.…”

Section: Discussionsupporting

confidence: 57%

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Abildayeva

Jansen

Hirsch‐Reinshagen

et al. 2006

Journal of Biological Chemistry

218

188

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Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has beenhypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose-and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10 -20-fold higher basal LXR␣ and -␤ expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.

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Section: Discussionsupporting

confidence: 57%

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Abildayeva

Jansen

Hirsch‐Reinshagen

et al. 2006

Journal of Biological Chemistry

218

188

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“…Deletion of CYP27 does not induce atherosclerosis in mice [53][54][55] only in men [45,46]. LXR can induce its own transcription only in human cells [26,56,57]. AIM is regulated by LXR only in mice [37].…”

Section: Summary Of the Roles Of Ppars And Lxr In Lipid Metabolism Ofmentioning

confidence: 99%

Nuclear receptors in macrophages: A link between metabolism and inflammation

Szántó

Röszer

2007

FEBS Letters

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Subclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of atherosclerosis. A central role for activated macrophages has been elucidated recently as important regulators of the inflammatory process in atherosclerosis. Macrophage differentiation and function can be modulated by a class of transcription factors termed nuclear receptors. These are activated by intermediary products of basic metabolic processes. In this review the contribution of peroxisome proliferator-activated receptors and liver X receptors to macrophage functions in inflammation and lipid metabolism will be discussed in light of their roles in macrophages during atherosclerosis.In the past decade much effort has been made to understand the mechanisms how lipids are handled by macrophages and how inflammation could promote the atherogenic process. Here, we also provide an overview of these two fields.

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“…Two types of LXRs exist, LXR␣ and LXR␤. LXR␣ is found at high levels in cholesterol-metabolizing tissues and its expression is acutely regulated (Whitney et al, 2001), while LXR␤ is ubiquitously expressed (Baranowski, 2008). Both LXRs act as cholesterol sensors and are activated by hydroxylated forms of cholesterol, leading to induction of genes that encode for proteins directly responsible for cholesterol export from the cell, such as apolipoprotein E (ApoE), ATP-binding cassette transporters (ABCA1, ABCG1), and sterol regulatory element-binding protein 1c (SREBP1c) (Zelcer and Tontonoz, 2006).…”

Section: Introductionmentioning

confidence: 99%

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Terwel¹,

Steffensen²,

Verghese³

et al. 2011

J. Neurosci.

168

115

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Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-␤ (A␤) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble A␤ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by A␤ disposal. Despite the profound effect on A␤ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar A␤. Conditioned medium from TO901317-treated ApoE Ϫ/Ϫ or LXR␣ Ϫ/Ϫ astrocytes did not increase phagocytosis of A␤. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and A␤ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXR␣ and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXR␣ activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar A␤ in response to treatment with TO901317.

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Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Cited by 146 publications

References 40 publications

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Nuclear receptors in macrophages: A link between metabolism and inflammation

Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

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