Cholesterol metabolism: physiological regulation and diseases

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset cardiovascular disease (CVD) but also fundamental cause other ailments. regulation in human an extremely complex process. Due to dynamic balance between synthesis, intake, efflux storage, generally remains secure. Disruption any these links likely have adverse effects on body. At present, increasing evidence suggests that abnormal closely related various diseases. However, exact mechanism by which contributes pathogenesis unclear, there are still unknown factors. In this review, we outline metabolic process body, especially reverse transport (RCT). Then, discuss separately impact common diseases potential therapeutic targets each disease, including CVD, tumors, neurological diseases, immune system end focus effect eye short, hope provide more new ideas treatment from perspective cholesterol.

Language: Английский

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DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: June 21, 2023

Abstract Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer’s disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls homeostasis, which was found to be downregulated in AD vulnerable regions and involved AD-related pathological activities. However, DHCR24 as potential therapeutic target for remains identified. In present study, we demonstrated role by employing delivery adeno-associated virus carrying gene into hippocampus 5xFAD mice. Here, mice had lower levels expression, loss alleviated overexpression. Surprisingly, cognitive impairment significantly reversed after DHCR24-based therapy. Moreover, revealed knock-in successfully prevented or pathology mice, including amyloid-β deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis apoptosis. conclusion, our results firstly value DHCR24-mediated regulation level promising treatment AD.

Language: Английский

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Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 4, 2024

Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused biallelic mutations DHCR24 encoding 3-β-hydroxysterol Δ-24-reductase. regarded as the key enzyme cholesterol synthesis in metabolism brain it catalyzes reduction Δ-24 double bond intermediates during biosynthesis. To date, 15 variants, detected 2 related 14 unrelated patients, have been associated with desmosterolosis disorder. Here, we describe proband harboring never-described homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed through biochemical assay. By using molecular dynamics simulation techniques, investigated impact this on protein stability interaction network flavin adenine dinucleotide cofactor, thereby providing preliminary assessment its mechanistic role comparison all known pathogenic wild-type protein, benign variant. This report expands clinical spectra DHCR24-related disorder, reports novel deleterious desmosterolosis, gives new insights into genotype–phenotype correlations.

Language: Английский

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Integrating amyloid and tau imaging with proteomics and genomics in Alzheimer’s disease

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(9), P. 101735 - 101735

Published: Sept. 1, 2024

Language: Английский

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Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer’s astrocytes

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: March 23, 2024

Abstract Alzheimer’s disease (AD) is the most common cause of dementia, and its underlying mechanisms have been a subject great interest. The mainstream theory AD pathology suggests that primarily associated with tau protein amyloid-beta (Aβ). However, an increasing body research has revealed abnormalities in lipid metabolism may be important event throughout pathophysiology AD. Astrocytes, as members network brain, play significant role this event. study abnormal astrocytes provides new perspective for understanding pathogenesis This review focuses on fatty acids (FAs) cholesterol AD, discusses it from three perspectives: uptake, intracellular breakdown or synthesis metabolism, efflux transport. We found that, despite accumulation their own acids, cannot efficiently uptake neurons, leading to acid within neurons resulting lipotoxicity. In terms exhibit decrease endogenous due exogenous cholesterol. Through thorough investigation these metabolic abnormalities, we can provide insights future therapeutic strategies by literature navigate complex maze bring hope patients disease.

Language: Английский

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Multiomics analysis to explore blood metabolite biomarkers in an Alzheimer’s Disease Neuroimaging Initiative cohort

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 2, 2024

Alzheimer's disease (AD) is a neurodegenerative that commonly causes dementia. Identifying biomarkers for the early detection of AD an emerging need, as brain dysfunction begins two decades before onset clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra 39,108 unique biomolecules. Metabolic profiles 93 hydrophilic metabolites were determined. Additionally, integrated targeted lipidomic (4873 samples 1524 patients) to explore candidate predicting progressive mild cognitive impairment (pMCI) diagnosed within years baseline metabolome. Patients lower ergothioneine levels had 12% higher rate progression significance P = 0.012 (Wald test). Furthermore, increase ganglioside (GM3) and decrease plasmalogen lipids, many which are associated apolipoprotein E polymorphism, confirmed patients, lysophosphatidylcholine (18:1) GM3 d18:1/20:0 showed 19% 17% rates progression, respectively test: 3.9 × 10-8 4.3 10-7). Palmitoleamide, oleamide, diacylglycerols, ether lipids also identified significantly altered at pMCI. The analysis genomics combining information on genotypes enhances predictive performance suggesting metabolomics essential complement genomic data. In conclusion, reanalysis multiomics provides new insights detect development pathology partially understand metabolic changes age-related AD.

Language: Английский

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Vitamin D, a Secosteroid Hormone and Its Multifunctional Receptor, Vitamin D Receptor, in Alzheimer’s Type Neurodegeneration

Journal of Alzheimer s Disease, Journal Year: 2023, Volume and Issue: 95(4), P. 1273 - 1299

Published: Sept. 1, 2023

Vitamin D is a secosteroid hormone exerting neurosteroid-like properties. Its well-known nuclear receptor, and recently proposed as mitochondrial transcription factor, vitamin acts for its primary functions. The second receptor an endoplasmic reticulum protein, protein disulfide isomerase A3 (PDIA3), suggested to act rapid response. has effects on various systems, particularly through calcium metabolism. Among them, the nervous system important place in context of our subject. Recent studies have shown that receptors numerous system. Neurodegeneration long-term process. Throughout human life span, so deficiency. Our previous others out-come deficiency (hypovitaminosis or inefficient utilization D), may lead neurons be vulnerable aging neurodegeneration. We suggest keeping levels at adequate all stages life, considering new approaches such agonists can activate receptors, utilizing other derivatives produced synthesis process with UVB are crucial when D-based intervention studies. Given most aspects D, this review outlines how work involved neurodegeneration, emphasizing Alzheimer’s disease.

Language: Английский

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Enhanced neuroprotective effect of verapamil-loaded hyaluronic acid modified carbon quantum dots in an in-vitro model of amyloid-induced Alzheimer's disease

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 275, P. 133742 - 133742

Published: July 8, 2024

Language: Английский

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High mRNA Expression of 24 Dehydrocholesterol Reductase (DHCR24) in the Treatment of Doxorubicin-Induced Heart Failure in Rats

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 312 - 312

Published: Jan. 1, 2025

Objective: The objective of this study was to explore the possibility treating heart failure in rats by delivering mRNA 24-dehydrocholesterol reductase (DHCR24) into body through lipid nanoparticles (LNPs). Methods: We established a rat model using doxorubicin. experiment divided blank, model, stock solution cardiac injection, intravenous LNP-mRNA and injection groups. directly injected DHCR24-mRNA or LNP-DHCR24-mRNA myocardium three regions an insulin needle passing intercostal space under guidance B-ultrasound. recorded mortality rate, weight, 6-min walk test return times, organ weight after administration detected structure function B-ultrasound transmission electron microscopy (TEM). Additionally, we tested for HE staining; PRDX2, Sirt3, TRX1 protein expression; IL-1 β, IL-10, VEGF, NT proBNP, BNP cytokine concentrations. Results: Compared with group, significantly reduced mortality; decreased loss, ratio tibia length, spleen weight; improved motility. can postpone pathological morphological alterations myocardial cells reduce inflammatory infiltration. In terms biochemistry, increase expression proteins; concentrations IL-10 VEGF; IL-1β, BNP. also delay process failure. delivery therapeutic effect encapsulated LNPs were better when compared other Conclusions: be effectively administered exhibits some curative effects.

Language: Английский

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Cellular Cholesterol Loss Impairs Synaptic Vesicle Mobility via the CAMK2/Synapsin-1 Signaling Pathway

Frontiers in Bioscience-Landmark, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 20, 2025

Background: Neuronal cholesterol deficiency may contribute to the synaptopathy observed in Alzheimer’s disease (AD). However, underlying mechanisms remain poorly understood. Intact synaptic vesicle (SV) mobility is crucial for normal function, whereas disrupted SV can trigger associated with AD. In this study, we investigated whether cellular affects mobility, aim of identifying mechanism that links loss Methods: Lentiviruses carrying 3β-hydroxysteroid-Δ24 reductase-complementary DNA (DHCR24-cDNA), DHCR24-short hairpin RNA (DHCR24- shRNA) or empty lentiviral vectors were transfected into SHSY-5Y cells order construct DHCR24 knock-down and knock-in models, along corresponding controls. Filipin III staining was employed visualize membrane intracellular different cell fluorescence intensity assessed using confocal microscopy. Additionally, performed immunoblotting quantify expression DHCR24, total calmodulin-dependent protein kinase 2 (CAMK-2), p-CAMK2 (T286), caveolin-1, synapsin-1, phosphorylated synapsin-1 (p-synapsin-1; S605), synaptophysin each experimental group. Results: DHCR24-silenced cells, caused by DCHR24 resulted a significant decrease levels CAMK2 (p-CAMK2) (p-synapsin-1) compared control cells. The reduction p-synapsin-1 could disrupt thereby reducing replenishment readily releasable pool (RRP) from reserve (RP). Furthermore, showed downregulation lipid raft marker, Conversely, elevated reversed effects deficiency, suggesting CAMK2-mediated phosphorylation be regulated raft-associated manner. found significantly downregulate protein, which vital biogenesis plasticity. Conclusion: These results suggest depletion following impair regulating CAMK2-meditated pathway, potentially via mechanism. Our study indicates critical role AD-related synaptopathy, thus highlighting potential targeting metabolism therapeutic strategies.

Language: Английский

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