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LXR Agonists: New Potential Therapeutic Drug for Neurodegenerative Diseases

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Abstract

Liver X receptors (LXRs) are nuclear receptors involved in the regulation of lipid metabolism and inflammatory responses in the central nervous system. Defects in cholesterol homeostasis contribute to the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Inflammatory responses could enhance the neurodegenerative process or act independently. The natural and synthetic LXR agonists induce the transcriptional activity of LXR target genes, thus attenuate the imbalance of cholesterol metabolism and overactivation of microglia and astrocytes in inflammation and are widely used in a variety of neurodegenerative diseases animal models. By developing more specific, potent, penetrable, and functional LXR agonist may lead to a better curative effect for neurodegenerative diseases and avoidance of potentially deleterious side effects. Here, we focus on recent advances in our understanding of the role of LXRs and their agonists in cholesterol homeostasis, inflammation, and the potential therapeutic effects in neurodegenerative diseases.

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Abbreviations

24OHC:

24(S)-Hydroxycholesterol

22OHC:

22(R)-Hydroxycholesterol

24,25OHC:

24(S),25-Epoxycholesterol

27OHC:

27-Hydroxycholesterol

3βHSD:

3b-Hydroxysteroid dehydrogenase

ABC:

ATP-binding cassette

ACC:

Acetyl CoA carboxylase

ApoE:

Apolipoprotein E

ChREBP:

Carbohydrate responsive element binding protein

COX-2:

Cyclooxygenase-2

CYP11A1:

Cytochrome P450 side-chain cleavage

ENG:

Endoglin/CD105

FAS:

Fatty acid synthase

F1–6B:

Fructose 1,6 biphosphatase

Glut4:

Glucose transporter 4

G6P:

Glucose-6-phosphatase

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

LXRE:

LXR response element

PEPK:

Phosphoenolpyruvate kinase

SCD1:

Stearoyl-CoA desaturase 1

SREBP1c:

Sterol regulatory element binding protein 1c

StAR:

Steroidogenic acute regulatory protein.

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Acknowledgments

This study was supported by National Basic Research Program of China (no. 2013CB967002) and National Nature Science Foundation of China (nos. 31070927, 31271051).

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Authors and Affiliations

  1. Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Pei Xu, Xiaotong Tang, Yang Yang & Xiaotang Fan

  2. Department of Physiology, Luzhou Medical College, Luzhou, 646000, People’s Republic of China

    Dabing Li

  3. Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Xiaohang Bao & Jing Huang

  4. Southwest Eye Hospital, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Yongping Tang & Haiwei Xu

  5. Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, People’s Republic of China

    Yongping Tang & Haiwei Xu

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  1. Pei Xu
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Correspondence to Haiwei Xu or Xiaotang Fan.

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Xu, P., Li, D., Tang, X. et al. LXR Agonists: New Potential Therapeutic Drug for Neurodegenerative Diseases. Mol Neurobiol 48, 715–728 (2013). https://doi.org/10.1007/s12035-013-8461-3

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