TY - JOUR
T1 - Liver X receptor β (LXRβ)
T2 - A link between β-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia
AU - Kim, Hyun Jin
AU - Fan, Xiaotang
AU - Gabbi, Chiara
AU - Yakimchuk, Konstantin
AU - Parini, Paolo
AU - Warner, Margaret
AU - Gustafsson, Jan Åke
PY - 2008/2/12
Y1 - 2008/2/12
N2 - Administration of β-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXRβ-/- 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, β-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXRβ-/- mice. WT mice were not affected by these doses of β-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) β and/or treatment with β-sitosterol nor were there changes in plasma levels of cholesterol or β-sitosterol. In 8-month-old LXRβ-/- 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 LXRβ-/- than in their WT counterparts, and treatment with β-sitosterol reduced brain cholesterol in both WT and LXRβ-/- mice. In LXRβ-/- mice but not in WT mice levels of 24-hydrocholesterol were increased upon β-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXRβ-/- mice to β-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.
AB - Administration of β-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXRβ-/- 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, β-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXRβ-/- mice. WT mice were not affected by these doses of β-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) β and/or treatment with β-sitosterol nor were there changes in plasma levels of cholesterol or β-sitosterol. In 8-month-old LXRβ-/- 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 LXRβ-/- than in their WT counterparts, and treatment with β-sitosterol reduced brain cholesterol in both WT and LXRβ-/- mice. In LXRβ-/- mice but not in WT mice levels of 24-hydrocholesterol were increased upon β-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXRβ-/- mice to β-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.
KW - Central nervous system
KW - Cholesterol
KW - Microglia
KW - Neurodegenerative disease
KW - Nuclear receptor
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U2 - 10.1073/pnas.0711599105
DO - 10.1073/pnas.0711599105
M3 - Article
C2 - 18238900
AN - SCOPUS:41149111376
SN - 0027-8424
VL - 105
SP - 2094
EP - 2099
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -