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

Wang, Ling; Schuster, Gertrud U.; Hultenby, Kjell; Zhang, Qinghong; Andersson, Sandra; Gustafsson, Jan Åke

doi:10.1073/pnas.172510899

Cited by 251 publications

(217 citation statements)

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“…The role of LXRs in the CNS is less well understood. Our findings indicate that LXRs control both basal and inducible expression of a subset of genes important for cellular cholesterol homeostasis in the brain, in agreement with the findings of Wang et al (15). We have further shown that these genes are controlled in a receptor-dependent manner in primary glial cultures.…”

Section: Discussionsupporting

confidence: 93%

“…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.

299

214

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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: 93%

Section: Discussionsupporting

confidence: 89%

mentioning

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.

299

214

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“…Interestingly, PPARγ, which is also expressed by oligodendrocyte lineage cells, has been shown to accelerate oligodendrocyte differentiation when it is activated [73]. Moreover, deletion of LXRγ and LXRβ in mice results in dysmyelination or myelin abnormalities [74]. Identification of the RXR heterodimeric partner would therefore improve our understanding of RXR signaling in oligodendrocyte lineage cells, and help develop more finely tuned agonists that would target oligodendrocytes specifically in remyelination therapy.…”

Section: Wnt Signalingmentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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“…LXRs are oxysterol activated nuclear receptors, which play an important part in the control of cellular and whole-body cholesterol homeostasis (Peet et al, 1998;Repa and Mangelsdorf, 2000). Absence of LXRs in mice leads to disorganized myelin sheaths, which indicates a role for the LXRs in OLG function (Wang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Selection of reference genes for gene expression studies in rat oligodendrocytes using quantitative real time PCR

Nelissen

Smeets

Mulder

et al. 2010

Journal of Neuroscience Methods

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Quantitative real time polymerase chain reaction (qPCR) has become a widely used tool to examine gene expression levels. Reliable quantification, however, depends on a proper normalization strategy. Normalization with multiple reference genes is becoming the standard, although the most suitable reference genes depend on the applied treatment as well as the tissue or cell type studied. In this study the stability of various reference genes was investigated in cultures of oligodendrocytes derived from either mature or neonatal rats, the latter also in the presence of the liver X receptor (LXR) agonist.The expression stability of ten commonly used reference genes (HPRT, GAPDH, 18S, ActB, CycA, Tbp, Rpl13A, YWHAZ, HMBS, Pgk1) was analyzed using geNorm and NormFinder.When comparing the different types of cell cultures, Rpl13A, CycA, Pgk1 and YWHAZ were identified as most stable genes. After LXR agonist treatment, CycA, Pgk1 and Rpl13A were found to be the most stable by both geNorm and NormFinder. HMBS and the commonly used housekeeping genes GAPDH and 18S turned out to be the most variable according to geNorm and NormFinder. In conclusion, the use of multiple reference genes, instead of only one, in qPCR experiments with rat oligodendrocytes is strongly advised and standard housekeeping genes such as GAPDH and 18S are not recommended as they appear to be relatively unstable under the experimental conditions used. Reference gene selection should always be performed for each individual experiment, since useful reference genes are very specific for every situation.

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

Cited by 251 publications

References 50 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

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

Selection of reference genes for gene expression studies in rat oligodendrocytes using quantitative real time PCR

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