Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
Abstract
The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS disea…
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Intracellular cholesterol accumulation provides a potential explanation for the reduced nuclear localization of Srebp2 in Mecp2 KO astrocytes, given negative feedback.
“Notably, the accumulation of intracellular cholesterol provides a potential explanation for the reduced nuclear localization of Srebp2 observed in KO astrocytes, given the negative feedback exerted by intracellular cholesterol on Srebp2 activation (Duan et al., 2022;N.-Q. Wang et al., 2025).”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as N.-Q. Wang et al., 2025
Intracellular cholesterol inhibits Srebp2 activation through a negative feedback mechanism.
“However, intracellular cholesterol is known to inhibit Srebp2 activation through a negative feedback mechanism (Duan et al., 2022;Wang et al., 2025).”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Wang et al., 2025
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Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome
Postogna, F. M., Giancroce, N., Cabasino, C., Biella, F., Roggero, O. M., Breccia, M., Morelli, L., Colombo, D., Arcari, A., Lunghi, G., et al. (2026) · doi:10.64898/2026.07.29.741426 · Cited by 1 · see citing works
“Notably, the accumulation of intracellular cholesterol provides a potential explanation for the reduced nuclear localization of Srebp2 observed in KO astrocytes, given the negative feedback exerted by intracellular cholesterol on Srebp2 activation (Duan et al., 2022; N.-Q. Wang et al., 2025).”
- Authors
- Wang, N.-Q., Sun, P.-X., Shen, Q.-Q., & Deng, M.-Y.
- Affiliations
- Zhengzhou University (CN)
- Venue
- Molecular Neurobiology
- Published
- 2025-01-07
- Volume
- 62
- Issue
- 5
- Pages
- 6283-6307
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W4406120790
- Cited by
- 19
- References
- 28
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 1
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the Postdoctoral Science Foundation of China (2024M752949)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- cholesterol metabolism, central nervous system disorders, SREBP2, liver X receptor, Alzheimer's disease, Huntington's disease, multiple sclerosis, brain cholesterol homeostasis, cholesterol biosynthesis, reverse cholesterol transport, myelin, synapses, therapeutic target
- MeSH terms
- Liver X Receptors, Animals, Central Nervous System Diseases, Cholesterol, Humans, Lipid Metabolism, Sterol Regulatory Element Binding Protein 2, Molecular Targeted Therapy
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