Analysis of the protein network of cholesterol homeostasis in different brain regions: An age and sex dependent perspective
Abstract
Although a great knowledge about the patho-physiological roles of cholesterol metabolism perturbation in several organs has been reached, scarce information is available on the regulation of cholesterol homeostasis in the brain where this lipid is involved in the maintenance of several of neuronal processes. Currently, no study is available in literature dealing how and if sex and age may modulate the major proteins involved in the regulatory network of cholesterol levels in different brain regions. Here, we investigated the behavior of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGR) and low-density lipoprotein receptor (LDLr) in adult (3-month-old) and aged (12-month-old) male and female rats. The analyses were performed in four different brain regions: cortex, brain stem, hippocampus, and cerebellum which represent brain areas characterized by different neuronal cell types, metabolism, cytoarchitecture and white matter composition. The results show that in hippocampus HMGR is lower (30%) in adult female rats than in age-matched males. Differences in LDLr expression are also observable in old females with respect to age-matched males: the protein levels increase (40%) in hippocampus and decrease (20%) in cortex, displaying different mechanisms of regulation. The mechanism underlying the observed modifications are ascribable to Insig-1 and SREBP-1 modulation. The obtained data demonstrate that age- and sex-related differences in cholesterol homeostasis maintenance exist among brain regions, such as the hippocampus and the prefrontal cortex, important for learning, memory and affection. Some of these differences could be at the root of marked gender disparities observed in clinical disease incidence, manifestation, and prognosis.
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These changes suggest that low intracellular cholesterol content, as a consequence of HMGCR activity suppression in RTT fibroblasts, induces the classic feedback mechanism with activation of SREBP2 and the increase of its transcriptional targets such as LDLR and HMGCR.
“These changes suggest that low intracellular cholesterol content, as a consequence of HMGCR activity suppression in RTT fibroblasts, induces the classic feedback mechanism with activation of SREBP2 and the increase of its transcriptional targets such as LDLR (LDL receptor) and HMGCR [23,55,103,104,105,106,107].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [105]
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“Specifically, these signaling proteins undergo prenylation which consists of a covalent attachment of farnesyl or geranylgeranyl, two types of prenyls produced by the non-sterol isoprenoid pathway, a branch of the mevalonate (MVA) pathway which is the biochemical process synthesizing cholesterol (Figure 1) [18].”
BackgroundSelf-citation
- Authors
- Segatto, M., Di Giovanni, A., Marino, M., & Pallottini, V.
- Affiliations
- Roma Tre University (IT)
- Corresponding author
- Pallottini, Valentina
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2013-03-21
- Volume
- 228
- Issue
- 7
- Pages
- 1561-1567
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2012545977
- Cited by
- 52
- References
- 4
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 1 · 2014: 3 · 2013: 1
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Iris (Roma Tre University) (submittedVersion)
- 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 › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- cholesterol homeostasis, brain regions, sex differences, aging, HMG-CoA reductase, LDL receptor, INSIG1, SREBP1, hippocampus, prefrontal cortex, brainstem, cerebellum, lipid metabolism
- MeSH terms
- Aging, Animals, Brain, Brain Stem, Cerebellum, Cerebral Cortex, Cholesterol, Female, Hippocampus, Homeostasis, Hydroxymethylglutaryl CoA Reductases, Male, Membrane Proteins, Nerve Tissue Proteins, Receptors, LDL, Sex Characteristics, Tissue Distribution, Rats, Wistar, Intracellular Signaling Peptides and Proteins, Rats, Sterol Regulatory Element Binding Protein 1
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