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The Journal of Neuroscience, December 26, 2007, 27(52):14470-14480; doi:10.1523/JNEUROSCI.4823-07.2007

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Neurobiology of Disease
Liver X Receptor Activation Enhances Cholesterol Loss from the Brain, Decreases Neuroinflammation, and Increases Survival of the NPC1 Mouse

Joyce J. Repa,^1,2 * Hao Li,^1 * Tamy C. Frank-Cannon,² Mark A. Valasek,² Stephen D. Turley,¹ Malú G. Tansey,² and John M. Dietschy¹

¹Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75390-9151, and ²Department of Physiology, University of Texas Southwestern Medical School, Dallas, Texas 75390-9077

Correspondence should be addressed to either of the following: John M. Dietschy, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151, Email: john.dietschy{at}utsouthwestern.edu; or Joyce J. Repa, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077, Email: joyce.repa{at}utsouthwestern.edu

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 β (LXRβ), 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 µg 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, 3HSD, 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.

Key words: 24(S)-hydroxycholesterol; microglia; astroglia; blood–brain barrier; nuclear receptors; Purkinje cells

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Received Sept. 13, 2007; revised Nov. 16, 2007; accepted Nov. 16, 2007.

Correspondence should be addressed to either of the following: John M. Dietschy, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151, Email: john.dietschy{at}utsouthwestern.edu; or Joyce J. Repa, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077, Email: joyce.repa{at}utsouthwestern.edu

This article has been cited by other articles:

				H. Li, S. D. Turley, B. Liu, J. J. Repa, and J. M. Dietschy GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice J. Lipid Res., August 1, 2008; 49(8): 1816 - 1828. [Abstract] [Full Text] [PDF]

				S. K. Erickson Genes, environment, and lifespan: new insights into Niemann-Pick C disease J. Lipid Res., March 1, 2008; 49(3): 497 - 498. [Full Text] [PDF]

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