Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals

Steffensen, Knut R.; Neo, Soek Ying; Stulnig, Thomas M.; Vega, Vinsensius B.; Rahman, Safia S; Schuster, Gertrud U.; Gustafsson, Jan‐Åke; Liu, Edison T.

doi:10.1677/jme.1.01508

Cited by 47 publications

(43 citation statements)

References 48 publications

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“…Data represent means Ϯ SEM. Scale bars, 100 m. berti et al, 2000Wang et al, 2002;Steffensen et al, 2004;Andersson et al, 2005;Kim et al, 2008). Moreover, even though the affinity of TO901317 for LXR␣ and LXR␤ may not be different, the biological effects of TO901317 often indicate a greater action through LXR␣ (Fiévet and Staels, 2009), whereas, at least in hepatocytes and astrocytes, the abundance of LXR␤ is even greater than that of LXR␣ (Tobin et al, 2000;Abildayeva et al, 2006).…”

Section: Apoe-dependent Microglial Phagocytosis Of Fibrillar A␤ Contrmentioning

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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Section: Apoe-dependent Microglial Phagocytosis Of Fibrillar A␤ Contrmentioning

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

View full text Add to dashboard Cite

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“…LXRβ is one of the two members of this subfamily, which has irreplaceable functions in the central nervous system (20)(21)(22)(23)(24). We previously showed that LXRβ expression is essential for the maintenance of motor neurons in the spinal cord and dopaminergic neurons in the substantia nigra (25,26).…”

mentioning

confidence: 99%

Anxiety in liver X receptor β knockout female mice with loss of glutamic acid decarboxylase in ventromedial prefrontal cortex

Tan

Dai

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Anxiety disorders are the most prevalent mental disorders in adolescents in the United States. Female adolescents are more likely than males to be affected with anxiety disorders, but less likely to have behavioral and substance abuse disorders. The prefrontal cortex (PFC), amygdala, and dorsal raphe are known to be involved in anxiety disorders. Inhibitory input from the PFC to the amygdala controls fear and anxiety typically originating in the amygdala, and disruption of the inhibitory input from the PFC leads to anxiety, fear, and personality changes. Recent studies have implicated liver X receptor β (LXRβ) in key neurodevelopmental processes and neurodegenerative diseases. In the present study, we used elevated plus-maze, startle and prepulse inhibition, open field, and novel object recognition tests to evaluate behavior in female LXRβ KO (LXRβ −/− ) mice. We found that the female LXRβ −/− mice were anxious with impaired behavioral responses but normal locomotion and memory. Immunohistochemistry analysis revealed decreased expression of the enzyme responsible for GABA synthesis, glutamic acid decarboxylase (65+67), in the ventromedial PFC. Expression of tryptophan hydroxylase 2 in the dorsal raphe was normal. We conclude that the anxiogenic phenotype in female LXRβ −/− mice is caused by reduced GABAergic input from the ventromedial PFC to the amygdala.

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“…Their endogenous ligands are oxysterols (24,25). Studies on LXR␣ and LXR␤ knockout mice have revealed that LXR␣ but not LXR␤ plays an important role in cholesterol homeostasis, whereas LXR␤ has key functions in the immune system and CNS (26)(27)(28)(29)(30). LXR␤ mRNA is widely expressed in the fetal rat brain, but in the postnatal and adult brains it is more discretely localized (31).…”

mentioning

confidence: 99%

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Kim¹,

Fan²,

Gabbi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

129

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Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

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Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals

Cited by 47 publications

References 48 publications

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

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

Anxiety in liver X receptor β knockout female mice with loss of glutamic acid decarboxylase in ventromedial prefrontal cortex

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

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