Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System

Whitney, Karl; Watson, Michael A.; Collins, Jon L.; Benson, William G.; Stone, Tammy M.; Numerick, Mary Jo; Tippin, Timothy K.; Wilson, Joan G.; Winegar, Deborah A.; Kliewer, Steven A.

doi:10.1210/mend.16.6.0835

Cited by 159 publications

(108 citation statements)

References 48 publications

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“…Decreased lipidation of apoE-containing lipoproteins has been proposed to underlie the decreased stability of apoE and its deposition in ABCA1-null mice. Despite the fact that the Apoe gene is a target for LXR (35), we observed no effect of LXR on Apoe gene expression in whole brain, consistent with previous work (12,15). It is plausible, however, that LXR activation may alter the posttranslational stability of apoE by regulating its ABCA1-dependent lipidation.…”

Section: Discussionsupporting

confidence: 89%

“…The function of LXRs in the brain is not well understood. Ligand activation of LXRs promotes cholesterol efflux from glia (12,13) and primary neurons (14), whereas mice deficient in expression of Lxr␣ and Lxr␤ develop marked accumulation of neutral lipids in the brain (15). Functionally, loss of LXR␤ leads to adult-onset motor neuron degeneration by the age of 7 months (16).…”

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confidence: 99%

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Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Zelcer

Khanlou

Clare

et al. 2007

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

305

224

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Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxr␣ or Lxr␤ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid ␤ peptide (fA␤) in a receptordependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fA␤-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.T he liver x receptors ␣ and ␤ (LXR␣/NR1H3 and LXR␤/ NR1H2, respectively) are oxysterol-activated nuclear receptors that play an important role in the control of cellular and whole-body cholesterol homeostasis (1-4). LXRs are also potent inhibitors of inflammatory responses in macrophages, pointing to an additional function for LXR signaling in immune regulation (5-11). The function of LXRs in the brain is not well understood. Ligand activation of LXRs promotes cholesterol efflux from glia (12, 13) and primary neurons (14), whereas mice deficient in expression of Lxr␣ and Lxr␤ develop marked accumulation of neutral lipids in the brain (15). Functionally, loss of LXR␤ leads to adult-onset motor neuron degeneration by the age of 7 months (16). The role of LXRs in human neurodegenerative diseases, however, remains largely unknown.Alzheimer's disease (AD) is an age-dependent neurodegenerative disease typified by progressive neuronal loss and cognitive impairment. AD is characterized by extraneuronal deposits of ␤-amyloid (A␤) fibrils (fA␤) (17) and intraneuronal tangles of hyperphosphorylated (18). The identification of rare mutations in the amyloid precursor protein (APP) and in presenilin genes (PS) in human AD is consistent with a central role for A␤ in AD pathogenesis (19). AD is a multifactorial disease, and inflammatory processes and cholesterol metabolism are among several factors that have been linked to its etiology.The AD brain exhibits prominent activation of innate immune responses. For example, elevated levels of inflammatory mediators can be measured in AD brains, and these are postulated to contribute to neuronal loss. The local inflammatory response is mediated by activated microglia and reactive astrocytes that surround the senile plaques (20,21). Interaction of microglia with fA␤ leads to their activation and the release of an arra...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Zelcer

Khanlou

Clare

et al. 2007

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

305

224

View full text Add to dashboard Cite

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“…Consistent with a prior report, T0901317 also activated mPXR with an EC 50 of 0.075 M (Fig. 7B), which is well below the tissue concentration achieved at 50 mg͞kg per day of dosing (17). Activation by ALLO enantiomers was specific for PXR, because these compounds were unable to activate other nuclear receptors in in vitro reporter assays (M. Ricketts, D. Moore, and D.S.O., unpublished results).…”

Section: T0901317 and Allo Attenuate Microglial Infiltration And Purksupporting

confidence: 91%

“…3 and 9B). These observations suggest that dietary T0901317 (50 mg͞kg per day) achieves sufficient drug levels in cerebellar tissue of the npc1 Ϫ/Ϫ mice to activate LXR target genes and is in agreement with earlier in vivo studies with T0901317 (17).…”

Section: T0901317 and Allo Therapy Improves Function And Survival Insupporting

confidence: 91%

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

Langmade

Gale

Frolov

et al. 2006

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

152

145

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Niemann-Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum. We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the npc1 ؊/؊ mouse model. We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of npc1 ؊/؊ mice. ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue. To establish whether the mechanism of neuroprotection in npc1 ؊/؊ mice involves GABAA receptor activation, we compared treatment of natural ALLO and ent-ALLO, a stereoisomer that has identical physical properties of natural ALLO but is not a GABA A receptor agonist. ent-ALLO provided identical functional and survival benefits as natural ALLO in npc1 ؊/؊ mice, strongly supporting a GABAA receptor-independent mechanism for ALLO action. On the other hand, the efficacy of ALLO, ent-ALLO, and T0901317 therapy correlated with the ability of these compounds to activate pregnane X receptor-dependent pathways in vivo. These findings suggest that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease.cholesterol ͉ neurosteroid ͉ allopregnanolone ͉ neurodegeneration N iemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system and patterned Purkinje cell death in the cerebellum (1). Mutations in the NPC1 gene are responsible for Ϸ95% of human NPC disease. NPC1 loss-of-function mutants exhibit marked impairment of low-density lipoprotein (LDL) cholesterol esterification and mobilization of newly hydrolyzed LDL cholesterol to the plasma membrane (2-4), resulting in lysosomal sequestration of LDL cholesterol, delayed down-regulation of the LDL receptor and de novo cholesterol biosynthesis, and impaired ABCA1-mediated cholesterol efflux (5-7). Despite recent progress in characterizing the biochemical and genetic defects in NPC disease, the mechanisms underlying the neurodegenerative phenotype are not well understood. Moreover, at present there are no effective therapies that delay progression of human NPC disease.Many of the prominent neuropathological features of human NPC disease [e.g., neuronal lipid storage and progressive loss of Purkinje neurons (1)] are recapitulated in the BALB͞c NPC nih (npc1 Ϫ/Ϫ ) mouse, a naturally occurring murine model that harbors a retroposon insertion in the Npc1 gene (8, 9). In NPC1 mice, accumulation of unesterified cholesterol and gangliosides occurs in morphologically normal neurons as early as postnatal day 9 (P9) and precedes neuronal injury and c...

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“…In primary astrocyte cultures, but not in primary neuronal cultures, LXR agonists enhance cholesterol efflux and regulate several established LXR target genes. Induction of these target genes was also confirmed by treating animals with LXR agonists (22).…”

mentioning

confidence: 80%

Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration

Wang

Schuster

Hultenby

et al. 2002

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

256

217

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Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System

Cited by 159 publications

References 48 publications

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration

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