Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia
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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.
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“(2014), http://dx.doi.org/10.1016/j.nbd.2014.04.001), the discovery that LXRα/β have a role in AD pathogenesis and other forms of neurodegeneration (Andersson et al., 2005; Kim et al., 2008; Wang et al., 2002; Zelcer et al., 2007), and positive results of experimental treatment in AD mice.”
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- Authors
- Kim, H.-J., Fan, X., Gabbi, C., Yakimchuk, K., Parini, P., Warner, M., & Gustafsson, J.-Å.
- Affiliations
- Karolinska Institutet (SE)
- Departments of *Biosciences and Nutrition and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-02-12
- Volume
- 105
- Issue
- 6
- Pages
- 2094-2099
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2542868
- OpenAlex
- W2089971899
- Cited by
- 136
- References
- 54
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 13 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 12 · 2014: 6 · 2013: 7 · 2012: 9
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission (LSHM-CT-2005-018652)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- liver X receptor beta, β-sitosterol, amyotrophic lateral sclerosis, Parkinson's disease, dopaminergic neuron death, motor neuron degeneration, microglial activation, TDP-43 aggregates, brain cholesterol, ABCG5/ABCG8, NPC1L1, dietary sterols
- MeSH terms
- Liver X Receptors, Amyotrophic Lateral Sclerosis, Animals, Cholesterol, DNA-Binding Proteins, Dopamine, Immunohistochemistry, Intestinal Mucosa, Male, Motor Neurons, Sitosterols, Spinal Cord, Substantia Nigra, Tyrosine 3-Monooxygenase, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, ATP-Binding Cassette Transporters, Parkinsonian Disorders, Mice, Orphan Nuclear Receptors
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