Cholesterol metabolism in neurons and astrocytes

Pfrieger, Frank W.; Ungerer, Nicole

doi:10.1016/j.plipres.2011.06.002

Cited by 500Cholesterol and Lipid MetabolismCancer, Lipids, and MetabolismLipid Membrane Structure and Behavior

Cholesterol metabolism in neurons and astrocytes

Pfrieger, Frank W., Ungerer, Nicole·2011·Progress in Lipid Research

DOI 10.1016/j.plipres.2011.06.002

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Abstract

Cells in the mammalian body must accurately maintain their content of cholesterol, which is an essential membrane component and precursor for vital signalling molecules. Outside the brain, cholesterol homeostasis is guaranteed by a lipoprotein shuttle between the liver, intestine and other organs via the blood circulation. Cells inside the brain are cut off from this circuit by the blood-brain barrier and must regulate their cholesterol content in a different manner. Here, we review how this is accomplished by neurons and astrocytes, two cell types of the central nervous system, whose cooperation is essential for normal brain development and function. The key observation is a remarkable cell-specific distribution of proteins that mediate different steps of cholesterol metabolism. This form of metabolic compartmentalization identifies astrocytes as net producers of cholesterol and neurons as consumers with unique means to prevent cholesterol overload. The idea that cholesterol turnover in neurons depends on close cooperation with astrocytes raises new questions that need to be addressed by new experimental approaches to monitor and manipulate cholesterol homeostasis in a cell-specific manner. We conclude that an understanding of cholesterol metabolism in the brain and its role in disease requires a close look at individual cell types.

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Circulating lipids are not in exchange with cerebrospinal fluid.
“However, circulating lipids are not in exchange with cerebrospinal fluid (Pfrieger and Ungerer, 2011).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Pfrieger and Ungerer, 2011
Cholesterol synthesized de novo within the CNS is transported via APOE- and/or APOJ-containing lipid nanodiscs.
“Instead, cholesterol synthesized de novo within the CNS is transported via APOE- and/or APOJ-containing lipid nanodiscs (LaDu et al., 1998; Pfrieger and Ungerer, 2011).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Pfrieger and Ungerer, 2011
Cholesterol present in the CNS must be synthesized in situ.
“Cholesterol present in the CNS must be synthesized in situ [13].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [13]
Neurons produce cholesterol during prenatal life and depend on cholesterol synthesis by astrocytes after birth.
“Several studies suggest that neurons produce cholesterol during prenatal life and depend on cholesterol synthesis by astrocytes after birth [12,13].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [13]
In the brain, cholesterol metabolism is almost completely separated from the rest of the body because the blood-brain barrier prevents the passage of peripheric lipoproteins.
“in this organ, cholesterol metabolism is almost completely separated from the rest of the body because the blood-brain barrier (BBB) prevents the passage of peripheric lipoproteins [45].”
From Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome (2022) · cites this paper as [45]

Newborn neurons must produce cholesterol in a cell-autonomous manner, but as they mature they outsource production to astrocytes.
“As cholesterol synthesis is a resource-expensive process, current data suggest that newborn neurons must produce cholesterol in a cell-autonomous manner, but as they mature they outsource production to astrocytes (reviewed in [160,191]).”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [160]
Desmosterol is the most prevalent intermediate produced by the primary cholesterol synthesis pathway in the adult brain.
“Desmosterol is the most prevalent intermediate produced by the primary cholesterol synthesis pathway in the adult brain33.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [33]
The inhibition of cholesterol biosynthesis in brains of Mecp2 null mice is likely because aberrant turnover results in cholesterol accumulation.
“The cholesterol biosynthesis pathway is inhibited in brains of null mice likely because aberrant turnover results in cholesterol accumulation33.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [33]
Desmosterol is produced primarily by astrocytes in the adult brain.
“Modulating cholesterol homeostasis and turnover in the brain also ameliorated motor symptoms in Mecp2 null mice: fluvastatin treatment affected the abundance of desmosterol, which is produced primarily by astrocytes in the adult brain33,47.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [33]
Abnormal brain cholesterol metabolism may be a critical link between loss of MECP2 function and neuronal and glial dysfunction.
“Given the diverse roles played by cholesterol in the nervous system, including membrane trafficking, signal transduction, myelin formation, dendrite remodeling, neuropeptide formation and synaptogenesis33, abnormal brain cholesterol metabolism may be a critical link between loss of MECP2 function and neuronal and glial dysfunction.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [33]
These LNPs undergo receptor-mediated endocytosis in neurons and glia cells where their lipid constituents are disassembled in lysosomes to supply these constituents to recipient cells.
“In turn, these LNPs undergo receptor-mediated endocytosis in neurons and glia cells where their lipid constituents are disassembled in lysosomes to supply these constituents to the recipient cells.22, 44–47”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [44]
Secreted ApoE is generally presumed to be converted into HDL-like LNPs by astrocytes.
“As the major lipid carrier in the brain, secreted ApoE is generally presumed to be converted into HDL-like LNPs by astrocytes.”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [44]
Astrocytes coordinate many aspects of brain lipid homeostasis.
“Astrocytes coordinate many aspects of brain lipid homeostasis (Pfrieger and Ungerer, 2011).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Pfrieger and Ungerer, 2011

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LIPID METABOLISM IN BRAIN DURING MYELINATION
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Authors: Pfrieger, F. W., & Ungerer, N.
Affiliations: Centre National de la Recherche Scientifique (FR)
Corresponding author: Pfrieger, Frank W.
ORCID: Pfrieger, Frank W.
Venue: Progress in Lipid Research
Publisher: Elsevier BV
Published: 2011-10
Volume: 50
Issue: 4
Pages: 357-371
ISSN: 0163-7827 (ISSN-L)
DOI: 10.1016/j.plipres.2011.06.002
OpenAlex: W2006161539
Cited by: 500
References: 338
Citations by year: 2026: 40 · 2025: 48 · 2024: 38 · 2023: 42 · 2022: 45 · 2021: 35 · 2020: 37 · 2019: 39 · 2018: 23 · 2017: 30 · 2016: 24 · 2015: 27 · 2014: 31 · 2013: 25 · 2012: 15
FWCI: 4.16
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Lipid Research (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
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 › Lipid Membrane Structure and Behavior
Keywords: cholesterol metabolism, cholesterol homeostasis, neurons, astrocytes, blood-brain barrier, metabolic compartmentation, cholesterol turnover, brain development
MeSH terms: Animals, Astrocytes, Biological Transport, Blood-Brain Barrier, Brain, Cells, Cultured, Cholesterol, Humans, Lipoproteins, Neurons, Organ Specificity, Gene Expression, Receptors, Lipoprotein, ATP-Binding Cassette Transporters, Lipid Metabolism

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Cholesterol metabolism in neurons and astrocytes

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