Liver X receptor β (LXRβ):: A link between β-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia
Liver X receptor β (LXRβ):: A link between β-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia
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DOI：
10.1073/pnas.0711599105
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发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Gustafsson, Jan-Ake
中科院分区：
文献类型：
--
作者：
Kim, Hyun-Jin;Fan, Xiaotang;Gustafsson, Jan-Ake
对8月龄雄性LXR β（-/-）小鼠给予β-谷甾醇（42 mg/kg/天）3周，导致脊髓腰区运动神经元死亡和黑质酪氨酸羟化酶阳性多巴胺能神经元丢失。在5个月大的小鼠中，β-谷甾醇没有观察到毒性，但在16个月大时，它会导致LXR β（-/-）小鼠的严重瘫痪和多巴胺能功能障碍的典型症状。WT小鼠不受这些剂量的β-谷甾醇的影响。在5个月大的小鼠中，肠道转运蛋白ABCG 5/8和尼曼-匹克C1样1的水平不受肝脏X受体（LXR）β缺失和/或β-谷甾醇治疗的影响，胆固醇或β-谷甾醇的血浆水平也没有变化。在8个月大的LXR β（-/-）小鼠中，黑质网状部中的小胶质细胞活化，腰椎脊髓中大运动神经元的细胞质中的泛素和TDP-43聚集。LXR β（-/-）小鼠的脑胆固醇浓度高于WT小鼠，用β-谷甾醇治疗可降低WT和LXR β（-/-）小鼠的脑胆固醇。在LXR β（-/-）小鼠中，但在WT小鼠中，β-谷甾醇治疗后24-氢胆固醇水平增加。这些数据表明，LXR β（-/-）小鼠对β-谷甾醇的敏感性涉及多种机制。这些包括小胶质细胞的激活、大运动神经元细胞质中蛋白质聚集体的积累以及脑胆固醇的消耗。
Administration of beta-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR beta(-/-) 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 LXR beta(-/-) 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 LXR beta(-/-) 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 LXR beta(-/-) than in their WT counterparts, and treatment with beta-sitosterol reduced brain cholesterol in both WT and LXR beta(-/-) mice. In LXR beta(-/-) 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 LXR beta(-/-) 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.