Lu Fuxin, Fan Shujuan, Romo Andrea R, Xu Duan, Ferriero Donna M, Jiang Xiangning
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
University of California Berkeley, Berkeley, CA, USA.
J Cereb Blood Flow Metab. 2021 Feb;41(2):312-323. doi: 10.1177/0271678X20911910. Epub 2020 Mar 13.
The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.
脑胆固醇周转的主要途径依赖于利用脑特异性细胞色素P450 46A1（CYP46A1）将其羟基化为24S-羟基胆固醇（24S-HC）。仅在脑内产生的24S-HC通常穿过血脑屏障进入循环系统，然后进入肝脏进行排泄；因此，血清24S-HC水平是脑内胆固醇代谢的一个指标。我们最近报道了新生小鼠脑缺氧缺血（HI）后CYP46A1的上调，以及血清24S-HC水平与急性脑损伤之间的相关性。在此，我们进行了一项纵向研究，以调查血清24S-HC浓度是否能预测长期的脑结构和功能结果。在出生后第9天遭受HI的小鼠中，HI后6小时和24小时血清24S-HC水平升高，并与组织学测量或T2加权MRI测量的梗死体积相关。24小时的水平与通过MBP免疫染色和髓鞘蓝染色定量的白质体积损失有关。在HI后6小时和24小时血清24S-HC较高的动物，与HI后35-40天运动和认知缺陷更严重的动物相对应。这些数据表明，24S-HC可能是一种用于评估新生儿HI脑损伤严重程度及相关功能损害的新型早期血液生物标志物。
