Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (6), p.2094-2099
• Main Authors: Kim, Hyun-Jin, Fan, Xiaotang, Gabbi, Chiara, Yakimchuk, Konstantin, Parini, Paolo, Warner, Margaret, Gustafsson, Jan-Åke
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - chemically induced; Animals; ATP-Binding Cassette Transporters - metabolism; Biological Sciences; Brain; Cholesterol - blood; Cholesterols; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Dopamine - metabolism; Immunohistochemistry; Intestines - metabolism; Liver; Liver X Receptors; Male; Mice; Mice, Knockout; Microglia; Motor neurons; Motor Neurons - drug effects; Motor Neurons - enzymology; Orphan Nuclear Receptors; Parkinsonian Disorders - etiology; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; Sitosterols - blood; Sitosterols - toxicity; Spinal cord; Spinal Cord - drug effects; Spinal Cord - pathology; Substantia nigra; Substantia Nigra - drug effects; Substantia Nigra - pathology; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0711599105

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.