Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia.
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.
Kim
Hyun-Jin
HJ
Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-14186 Stockholm, Sweden.
Fan
Xiaotang
X
Gabbi
Chiara
C
Yakimchuk
Konstantin
K
Parini
Paolo
P
Warner
Margaret
M
Gustafsson
Jan-Ake
JA
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced*; D000818:Animals; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology; D057093:Orphan Nuclear Receptors; D020734:Parkinsonian Disorders / Q000209:etiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D012855:Sitosterols / Q000097:blood / Q000633:toxicity*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012855:Sitosterols; C025473:gamma-sitosterol; D002784:Cholesterol; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine