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High fat diet induces brain injury and neuronal apoptosis via down-regulating 3-β hydroxycholesterol 24 reductase (DHCR24)

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Abstract

Hyperlipidemia (HLP) is one of the risk factors for memory impairment and cognitive impairment. However, its pathological molecular mechanism remained unclear. 3β-hydroxysterol Δ24- reductase (DHCR24) is a key enzyme in cholesterol synthesis and has been reported to decrease in the affected areas in the brain of neurodegenerative disorders. In this study, hyperlipidemic mouse model was established to study the effect of high blood lipid on brain. The data obtained from HPLC analysis demonstrated that the cholesterol level in the brain of mice with hyperlipidemia was significantly elevated compared to the control group. While the pathological damages were observed in both cerebral cortex and hippocampus in the brain of hyperlipidemic mice. Furthermore, the protein level of DHCR24 was downregulated accompanied by elevated ubiquitination level in the hyperlipidemic mice brain. The mouse neuroblastoma cells N2a were exposed to the excess cholesterol loading, the cells underwent apoptosis and the mRNA and protein of DHCR24 in cholesterol-loaded N2a cells were significantly reduced. In addition, the expression level of endoplasmic reticulum stress marker protein (Bip and Chop) was markedly increased in response to the cholesterol loading. More importantly, overexpression of DHCR24 in N2a reversed neuronal apoptosis induced by the cholesterol loading. Conclusively, these findings suggested that hyperlipidemia could cause brain tissue injuries via down-regulating DHCR24, and overexpression of DHCR24 may alleviate hyperlipidemia-induced neuronal cells damage by reversing the endoplasmic reticulum stress-mediated apoptosis.

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Acknowledgements

The authors greatly acknowledge the funding support for this study. In addition, we thank Dr. Muhammad Ishfaq (Huanggang Normal University) for his help in revising and improving the language expression in the manuscript.

Funding

The study was supported by a grant of National Natural Science Foundation of China (No. 31271494) and Liaoning provincial key R & D project (No. 2020JH2/10300114 and 2019JH8/10300057).

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Author notes

  1. Ziyin Lu and Haozhen Wang are co-first authors.

Authors and Affiliations

  1. The School of Life Science, Liaoning University, Chongshanzhong-Lu No.66, Huanggu-Qu, Shenyang, 110036, China

    Ziyin Lu, Haozhen Wang, Xiujin Zhang, Xiuting Huang, Shan Jiang & Xiuli Lu

  2. Department of Cell Biology and Genetics, School of Basic Medical Sciences, Shenyang Medical College, Huang-He-Bei-Dajie, No.146, Shenyang, 110034, China

    Yang Li, Ting Liu & Bing Gao

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  1. Ziyin Lu
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Contributions

Xiuli Lu and Bing Gao supervised the whole experiments. Ziyin Lu and Haozhen Wang, designed this study and contributed to the paper writing. Xiujin Zhang, Xiuting Huang, Shan Jiang, Chen Lu, Yang Li, and Ting Liu performed the practical work and completed the experiments. All authors have read and approved the final version of this manuscript to be published.

Corresponding authors

Correspondence to Xiuli Lu or Bing Gao.

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The present study was conducted in accordance with Laboratory Animal-Guideline for ethical review of animal welfare (GB/T 35,892–2018, National Standards of the People’s Republic of China).

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Lu, Z., Wang, H., Zhang, X. et al. High fat diet induces brain injury and neuronal apoptosis via down-regulating 3-β hydroxycholesterol 24 reductase (DHCR24). Cell Tissue Res 393, 471–487 (2023). https://doi.org/10.1007/s00441-023-03804-3

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  • DOI: https://doi.org/10.1007/s00441-023-03804-3

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