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24S-羟胆固醇生成酶完全缺失和部分缺失对小鼠行为和海马转录的影响。

Effects of Complete and Partial Loss of the 24S-Hydroxycholesterol-Generating Enzyme on Behavior and Hippocampal Transcription in Mouse.

机构信息

Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.

Taylor Family Institute for Innovative Psychiatry Research, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.

出版信息

Biomolecules. 2024 Feb 21;14(3):254. doi: 10.3390/biom14030254.

DOI:10.3390/biom14030254
PMID:38540675
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10968171/
Abstract

Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior.

摘要

脑胆固醇代谢产物包括神经甾体和氧化固醇，它们在细胞生理学中发挥着重要作用。在神经元中，胆固醇氧化产物 24S-羟基胆固醇（24S-HC）是信号转导和转录的调节剂。在这里，我们使用合成酶 CYP46A1 的全局和细胞选择性基因缺失来研究 24S-HC 缺失的行为效应。全局缺乏 CYP46A1 的小鼠在年轻时表现出活动减少，条件性恐惧记忆意外增加。尽管在 VGLUT1 阳性细胞中选择性缺失 CYP46A1 的小鼠中海马体 24S-HC 明显减少，但这些条件性敲除小鼠并未重现行为效应。全局敲除对选定的胆固醇代谢基因产生强烈的、发育依赖性的转录效应。这包括对肝 X 受体靶标的矛盾变化。同样，条件性敲除不足以重现大多数变化。总的来说，我们的结果强调了 24S-HC 在体内环境中的复杂作用，这些作用不能完全用已知的机制来预测。结果还表明，可能需要完全抑制酶活性才能对基因表达和行为产生可检测的、治疗相关的影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/f9ce54f195a3/biomolecules-14-00254-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/7d3a7bce5e03/biomolecules-14-00254-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/d37675e7be41/biomolecules-14-00254-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/68c8339d218d/biomolecules-14-00254-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/122a53822c9f/biomolecules-14-00254-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/03f7fe612df6/biomolecules-14-00254-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/d7979aa22284/biomolecules-14-00254-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/218f4eace45a/biomolecules-14-00254-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/a3c64cfcf53f/biomolecules-14-00254-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/f9ce54f195a3/biomolecules-14-00254-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/7d3a7bce5e03/biomolecules-14-00254-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/d37675e7be41/biomolecules-14-00254-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/68c8339d218d/biomolecules-14-00254-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/122a53822c9f/biomolecules-14-00254-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/03f7fe612df6/biomolecules-14-00254-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/d7979aa22284/biomolecules-14-00254-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/218f4eace45a/biomolecules-14-00254-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/a3c64cfcf53f/biomolecules-14-00254-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de2e/10968171/f9ce54f195a3/biomolecules-14-00254-g009.jpg

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