ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 144 citations in OpenAlex.
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- 27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.Science advances · 2024Article
- LXR agonism for CNS diseases: promises and challenges.Journal of neuroinflammation · 2024Review
- Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation of microglia polarization and synaptic plasticity via PI3K/AKT pathway.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Article
- Differently increased volumes of multiple brain areas inFrontiers in neuroanatomy · 2024Article
- Advances in research on potential therapeutic approaches for Niemann-Pick C1 disease.Frontiers in pharmacology · 2024Review
- Understanding and Treating Niemann-Pick Type C Disease: Models Matter.International journal of molecular sciences · 2020Review
- Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease.Journal of lipid research · 2020Article
- Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases.Frontiers in molecular biosciences · 2020Review
- Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann-Pick Disease Type C1.International journal of molecular sciences · 2019Review
- Lipid and Lipid Raft Alteration in Aging and Neurodegenerative Diseases: A Window for the Development of New Biomarkers.International journal of molecular sciences · 2019Review
- Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function.American journal of physiology. Gastrointestinal and liver physiology · 2018Article
- The formation of giant plasma membrane vesicles enable new insights into the regulation of cholesterol efflux.Experimental cell research · 2018Article
- Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes.Molecular metabolism · 2018Article
- Article
- Reversal of Pathologic Lipid Accumulation in NPC1-Deficient Neurons by Drug-Promoted Release of LAMP1-Coated Lamellar Inclusions.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Liver X receptors regulate cerebrospinal fluid production.Molecular psychiatry · 2016Article
- Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage.Journal of neuroinflammation · 2016Article
- Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Although cholesterol is a major component of the CNS, there is little information on how or whether a change in sterol flux across the blood-brain barrier might alter neurodegeneration. In Niemann-Pick type C (NPC) disease, a mutation in NPC1 protein causes unesterified cholesterol to accumulate in the lysosomal compartment of every cell, including neurons and glia. Using the murine model of this disease, we used genetic and pharmacologic approaches in an attempt to alter cholesterol homeostasis across the CNS. Genetic deletion of the sterol transporters ATP-binding cassette transporter A1 (ABCA1) and low-density lipoprotein receptor in the NPC1 mouse did not affect sterol balance or longevity. However, deletion of the nuclear receptor, liver X receptor beta (LXRbeta), had an adverse effect on progression of the disease. We therefore tested the effects of increasing LXR activity by oral administration of a synthetic ligand for this transcription factor. Treatment with this LXR agonist increased cholesterol excretion out of brain from 17 to 49 microg per day, slowed neurodegeneration, and prolonged life. This agonist did not alter synthesis of cholesterol or expression of genes associated with the formation of 24(S)-hydroxycholesterol or neurosteroids such as CYP46A1, 3alphaHSD, and CYP11A1. However, levels of the sterol transporters ABCA1 and ATP-binding cassette transporter G1 were increased. Concomitantly, markers of neuroinflammation, CD14, MAC1, CD11c, and inducible nitric oxide synthase, were reduced, and microglia reverted from their amoeboid, active form to a ramified, resting configuration. Thus, LXR activation resulted in increased cholesterol excretion from the brain, decreased neuroinflammation, and deactivation of microglia to slow neurodegeneration and extend the lifespan of the NPC1 mouse.
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