Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia.

Abstract

Administration of beta-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXRbeta-/- mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, beta-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXRbeta-/- mice. WT mice were not affected by these doses of beta-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) beta and/or treatment with beta-sitosterol nor were there changes in plasma levels of cholesterol or beta-sitosterol. In 8-month-old LXRbeta-/- mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXRbeta-/- than in their WT counterparts, and treatment with beta-sitosterol reduced brain cholesterol in both WT and LXRbeta-/- mice. In LXRbeta-/- mice but not in WT mice levels of 24-hydrocholesterol were increased upon beta-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXRbeta-/- mice to beta-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.

• Authors: Hyun-Jin Kim, Xiaotang Fan, Chiara Gabbi, Konstantin Yakimchuk, Paolo Parini, Margaret Warner, Jan-Ake Gustafsson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 6 Pg. 2094-9 (Feb 12 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18238900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• DNA-Binding Proteins
• Liver X Receptors
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear
• Sitosterols
• gamma-sitosterol
• Cholesterol
• Tyrosine 3-Monooxygenase
• Dopamine

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Amyotrophic Lateral Sclerosis (chemically induced)
• Animals
• Cholesterol (blood)
• DNA-Binding Proteins (genetics, physiology)
• Dopamine (metabolism)
• Immunohistochemistry
• Intestinal Mucosa (metabolism)
• Liver X Receptors
• Male
• Mice
• Mice, Knockout
• Motor Neurons (drug effects, enzymology)
• Orphan Nuclear Receptors
• Parkinsonian Disorders (etiology)
• Receptors, Cytoplasmic and Nuclear (genetics, physiology)
• Sitosterols (blood, toxicity)
• Spinal Cord (drug effects, pathology)
• Substantia Nigra (drug effects, pathology)
• Tyrosine 3-Monooxygenase (metabolism)