Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism
Open accessAbstract
Significance: Cholesterol is important for normal brain function and it is believed that astrocytes produce most brain cholesterol. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in the transcription factor sterol regulatory element-binding protein 2 (SREBP2). Using a mouse model in which SREBP2 has been knocked out in astrocytes, we show that astrocyte SREBP2 is required for normal brain development and behavior. Furthermore, this results in a shift in metabolism driven by increased brain glucose oxidation. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain development and function, and altered brain cholesterol synthesis may contribute to the interaction between diabetes and altered brain function.
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In mice, astrocyte-specific loss of Srebf2 resulted in reduced cholesterol synthesis and defects in neurite outgrowth, behavior, and energy metabolism.
“In mice, astrocyte-specific loss of Srebf2 resulted in reduced cholesterol synthesis and defects in neurite outgrowth, behavior, and energy metabolism (58).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [58]
The Discussion reports reduced astrocyte cholesterol synthesis and behavioral and metabolic changes in astrocyte-specific Srebf2 knockout mice. The neurite-outgrowth defect, however, was observed in an in-vitro coculture of mouse neurons with Srebf2-knockdown rat glioma cells, not in the knockout mice (SREBP2 in Astrocytes Is Required for Normal Neurite Outgrowth; page unavailable). (LLM, conf=0.90)
Experimental — accuracy not yet measuredDisruption of cholesterol biosynthesis in astrocytes alone directly impairs neurite outgrowth and synapse formation.
“Previous work identified a direct impairment of neurite outgrowth and synapse formation when cholesterol biosynthesis was disrupted in astrocytes alone, further highlighting the importance of astrocyte health and function in the context of neurodevelopment (Ferris et al., 2017).”
From Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk (2022) · cites this paper as Ferris et al., 2017
The neurite-outgrowth section reports reduced neurite growth when neurons were cocultured with SREBP2-knockdown glial cells. The Discussion links astrocyte cholesterol loss to reduced synapse quality and quantity as an inference, but does not report a direct measurement of impaired synapse formation. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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“Of the lipid classes that were not measured in the previous mouse study, we found that TGs and free fatty acids (FAs) were most abundant in iMicroglia. iAstrocytes had the highest CE stores, in line with the role of astrocytes as a cholesterol supplier for other brain cell types 49,50 .”
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“Additionally, reduced astrocytic cholesterol synthesis in young mice impairs neurodevelopment, leading to behavioural abnormalities, microencepha-lopathy, altered synaptic development, and other deficits [15–17].”
Elastin-Derived Peptides in the Central Nervous System: Friend or Foe
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Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference
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“We used [(13)C6] glucose as a tracer during the clamp and used tissue-specific 13C enrichments of alanine and glutamate to measure in vivo VPDH/VCS in soleus and quadriceps muscles (Alves et al., 2011; Ferris et al., 2017; Perry et al., 2018).”
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“Cholesterol is an integral part of any membrane, and the delivery of astroglial-derived cholesterol to neurons has been reported to be the limiting factor regulating synapse formation (Dietschy and Turley, 2001; Ferris et al., 2017).”
BackgroundThe role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis
White, C. J., Ellis, J. M., & Wolfgang, M. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100830 · Cited by 42 · see citing works
“Astrocytes have previously been characterized as important in other regards of brain lipid metabolism including being the main site of fatty acid oxidation (70) and cholesterol synthesis (71) within the CNS.”
BackgroundUlatowski, L. M., Ghelfi, M. D., West, R., Atkinson, J., Finno, C. J., & Manor, D. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101712 · Cited by 36 · see citing works
“Experimental perturbations to cholesterol transport in the brain were shown to cause impaired development and function of the brain (97, 98).”
BackgroundBalancing cholesterol in the brain: from synthesis to disposal
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“Curiously, mice with a loss of astrocytic SREBP2 display metabolic defects including adiposity reduction and a shift in their metabolism towards carbohydrate oxidation, driven by increased glucose oxidation by the brain [34].”
BackgroundQi, G., Mi, Y., & Yin, F. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2019.01531 · Cited by 37 · see citing works
Lipid droplet accumulation in microglia and their potential roles
Li, Y., Zhao, Q., Wang, Y., Du, W., Yang, R., Wu, J., & Li, Y. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02633-3 · Cited by 35 · see citing works
“However, astrocytes are absent in the embryonic brain [168, 169].”
Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders
Mitra, S., Banik, A., Saurabh, S., Maulik, M., & Khatri, S. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0998-21.2022 · Cited by 44 · see citing works
“An increase in brain glucose metabolism has been reported after astrocyte-selective knockdown of sterol-regulatory-element-binding protein 2, a receptor-bound transcription factor that regulates genes involved in cholesterol biosynthesis and uptake (Ferris et al., 2017).”
Bai, X., Wu, J.-F., Zhang, M., Xu, Y.-X., Duan, L.-J., Yao, K., Zhang, J.-F., Bo, J., Zhao, Y.-F., Xu, G.-X., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.513605 · Cited by 31 · see citing works
ALS-associated genes in SCA2 mouse spinal cord transcriptomes
Scoles, D. R., Dansithong, W., Pflieger, L. T., Paul, S., Gandelman, M., Figueroa, K. P., Rigo, F., Bennett, C. F., & Pulst, S. M. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa072 · Cited by 30 · see citing works
“Cholesterol cannot pass the blood– brain barrier; thus the brain must synthesize its own which is done in astrocytes, and when cholesterol synthesis is lost, neuronal dysfunction is the result (51).”
The Evolution of Cholesterol-Rich Membrane in Oxygen Adaption: The Respiratory System as a Model
Zuniga-Hertz, J. P., & Patel, H. H. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01340 · Cited by 32 · see citing works
Heterogeneity of Astrocyte Reactivity
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“In addition, cholesterol (Ferris et al., 2017) and myo- inositol (Haris et al., 2011) play roles in glial cell function; their increased abundance in the OB during aging may indicate involvement of glial cells.”
BackgroundNg, Y. P., Yip, T. F., Peiris, M. J. S., Ip, N. Y., & Lee, S. M.-Y. (2018) · Journal of NeuroVirology · doi:10.1007/s13365-018-0659-8 · Cited by 27 · see citing works
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“However, accumulating data suggests that ferrying the genes that are involved in cholesterol metabolism into mice brain could affect ADrelated pathology and cognitive activity [8, 22, 29, 76].”
BackgroundInsulin and IGF-1 elicit robust transcriptional regulation to modulate autophagy in astrocytes
Geffken, S. J., Moon, S., Smith, C. O., Tang, S. S., Lee, H. H., Lewis, K., Wong, C. W., Huang, Y., Huang, Q., Zhao, Y.-T., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101647 · Cited by 26 · see citing works
“Loss of cholesterol synthesis in astrocytes impairs normal brain development while also inducing cognitive dysfunction in mice [61].”
BackgroundCholesterol Metabolism in Neurodegenerative Diseases
He, K., Zhao, Z., Zhang, J., Li, D.-F., Wang, S., & Liu, Q. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2024.0674 · Cited by 24 · see citing works
“Loss of astrocytic SREBP2 functionally impairs neuronal dendrite outgrowth in vivo cocultures (Ferris et al., 2017), further emphasizing the necessity of astrocyte-derived cholesterol in maintaining normal neuronal function.”
Hypercholesterolemia and the Increased Risk of Vascular Dementia: a Cholesterol Perspective
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Function and therapeutic value of astrocytes in diabetic cognitive impairment
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Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline
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“Astrocytes supply much of the brain's required cholesterol (Björkhem & Meaney, 2004 ; Ferris et al., 2017; Zhang & Liu, 2015 ), yet astrocytes were notably absent from our cell-type deconvolu - tion results.”
BackgroundDefects of Nutrient Signaling and Autophagy in Neurodegeneration
Ondaro, J., Hernández-Eguiazu, H., Garciandia-Arcelus, M., Loera‐Valencia, R., Rodríguez-Gómez, L., Jiménez-Zúñiga, A., Goikolea, J., Rodriguez‐Rodriguez, P., Ruiz‐Martínez, J., Moreno, F., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.836196 · Cited by 27 · see citing works
“When cholesterol synthesis disruption causes neuronal function impairment, showing behavioral defects in mice (Ferris et al., 2017).”
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“Similarly, astrocytic expression of SREBF2 the central transcription factor coordinating the expression of cholesterol biosynthesis genes as well as SLC1A2 a glutamate transporter were shown to be essential for neuronal function an viability [51-53].”
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“…SREBP2 with a neuronal or an astrocytic marker (NeuN and GFAP, respectively), we found that the increased nuclear localization of SREBP2 was specific for glial cells (Fig 4J and K), the major producers of cholesterol in the adult brain (Mauch et al, 2001; Camargo et al, 2012; Ferris et al, 2017).”
BackgroundAPOE ε 4 and resting‐state functional connectivity in racially/ethnically diverse older adults
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Astrocyte involvement in metabolic regulation and disease
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Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
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“This is reduced with SREBP2 knockdown astrocytes; it also shows that mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor deficits [150].”
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Incretin-based therapeutics for the treatment of neurodegenerative diseases
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“https://doi.org/10.1038/s42255-025-01263-4 glucose sensing in the CNS and systemic glucose metabolism 50 , and is the main regulator of cholesterol synthesis in the brain 51 .”
InfluentialLange, J., Gillham, O., Flower, M. D., Ging, H., Eaton, S. D., Kapadia, S., Neueder, A., Duchen, M. R., Ferretti, P., & Tabrizi, S. J. (2023) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2023.102448 · Cited by 23 · see citing works
“Human HD astrocytes derived from PSC (pluripotent stem cells), such as embryonic (ESC) or induced pluripotent stem cell (iPSC), have been shown to mirror some phenotypes observed in post-mortem human HD brains, but have yet to be extensively studied (Cho et al., 2019; Garcia et al., 2019).”
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The Memory Orchestra: Contribution of Astrocytes
Chen, Y., Jin, S., Yang, J., & Gao, T. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01024-x · Cited by 22 · see citing works
Fernández-Gayol, O., Sanchis, P., Aguilar, K., Navarro-Sempere, A., Comes, G., Molinero, A., Giralt, M., & Hidalgo, J. (2019) · Neuroendocrinology · doi:10.1159/000496845 · Cited by 18 · see citing works
- Authors
- Ferris, H. A., Perry, R. J., Moreira, G. V., Shulman, G. I., Horton, J. D., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Yale University (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-01-17
- Volume
- 114
- Issue
- 5
- Pages
- 1189-1194
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5293102
- OpenAlex
- W2579178448
- Cited by
- 246
- References
- 43
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 34 · 2023: 37 · 2022: 29 · 2021: 25 · 2020: 29 · 2019: 19 · 2018: 5 · 2017: 4
- FWCI
- 15.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (5K08DK097293, R01 DK-40936, MMPC DK059635, R37DK031036)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- SREBP2, brain cholesterol, astrocyte-neuron co-culture, neurite outgrowth, brain development, motor defects, energy balance, body composition, glucose oxidation, brain metabolism, diabetes mellitus, metabolic disorders
- MeSH terms
- Animals, Astrocytes, Body Composition, Brain, Cholesterol, Energy Metabolism, Female, Glioma, Glucose, Hyperinsulinism, Male, Mice, Inbred C57BL, Neoplasm Proteins, Nesting Behavior, Oxidation-Reduction, Neurites, Mice, Knockout, Maze Learning, Rotarod Performance Test, Cell Line, Tumor, Mice, Rats, Sterol Regulatory Element Binding Proteins, Sterol Regulatory Element Binding Protein 2, Gene Knockdown Techniques
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