Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 2, 2022

Abstract Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative and cancers, particularly CVD which accumulation lipids (mainly cholesteryl esters) within macrophage/foam cells underneath endothelial layer drives formation atherosclerotic lesions eventually. More more studies have shown that lowering level, especially low-density lipoprotein protects system prevents events effectively. Maintaining is determined by biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All processes should be precisely controlled regulatory pathways. Based on regulation homeostasis, many interventions been developed to lower inhibiting biosynthesis uptake or enhancing utilization Herein, we summarize historical review research events, current understandings molecular pathways playing key regulating cholesterol-lowering clinics preclinical well new targets their clinical advances. importantly, discuss benefits those for treatment including obesity, diabetes, nonalcoholic fatty liver disease, cancer, osteoporosis virus infection.

Language: Английский

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Roles of bile acids signaling in neuromodulation under physiological and pathological conditions

Cell & Bioscience, Journal Year: 2023, Volume and Issue: 13(1)

Published: June 12, 2023

Abstract Bile acids (BA) are important physiological molecules not only mediating nutrients absorption and metabolism in peripheral tissues, but exerting neuromodulation effect the central nerve system (CNS). The catabolism of cholesterol to BA occurs predominantly liver by classical alternative pathways, or brain initiated neuronal-specific enzyme CYP46A1 mediated pathway. Circulating could cross blood barrier (BBB) reach CNS through passive diffusion transporters. Brain might trigger direct signal activating membrane nucleus receptors affecting activation neurotransmitter receptors. Peripheral may also provide indirect via farnesoid X receptor (FXR) dependent fibroblast growth factor 15/19 (FGF15/19) pathway takeda G protein coupled 5 (TGR5) glucagon-like peptide-1 (GLP-1) Under pathological conditions, alterations metabolites have been discovered as potential pathogenic contributors multiple neurological disorders. Attractively, hydrophilic ursodeoxycholic acid (UDCA), especially tauroursodeoxycholic (TUDCA) can exert neuroprotective roles attenuating neuroinflammation, apoptosis, oxidative endoplasmic reticulum stress, which provides promising therapeutic effects for treatment diseases. This review summarizes recent findings highlighting metabolism, crosstalk between periphery, functions elucidate role signaling under both conditions.

Language: Английский

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Cholesterol imbalance and neurotransmission defects in neurodegeneration

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(8), P. 1685 - 1690

Published: Aug. 1, 2024

The brain contains the highest concentration of cholesterol in human body, which emphasizes importance physiology. Cholesterol is involved neurogenesis and synaptogenesis, age-related reductions levels can lead to synaptic loss impaired plasticity, potentially contribute neurodegeneration. maintenance homeostasis neuronal plasma membrane essential for normal function, imbalances distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's Huntington's disease. This review aims explore molecular pathological mechanisms by imbalance neurotransmission defects neurodegeneration, focusing on four key mechanisms: (1) dysfunction, (2) alterations structure protein clustering, (3) oligomers amyloid beta (Aβ) protein, (4) α-synuclein aggregation.

Language: Английский

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Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

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Astrocytic contributions to Huntington's disease pathophysiology

Annals of the New York Academy of Sciences, Journal Year: 2023, Volume and Issue: 1522(1), P. 42 - 59

Published: March 2, 2023

Huntington's disease (HD) is a fatal, monogenic, autosomal dominant neurodegenerative caused by polyglutamine-encoding CAG expansion in the huntingtin (HTT) gene that results mutant proteins (mHTT) cells throughout body. Although large parts of central nervous system (CNS) are affected, striatum especially vulnerable and undergoes marked atrophy. Astrocytes abundant within contain mHTT HD, as well mouse models disease. We focus on striatal astrocytes summarize how they participate in, contribute to, molecular pathophysiology disease-related phenotypes HD model mice. Where possible, reference made to pertinent astrocyte alterations human HD. Astrocytic dysfunctions related cellular morphology, extracellular ion neurotransmitter homeostasis, metabolic support all accompany development progression both transgenic chimeric These findings reveal potential for therapeutic targeting so restore synaptic tissue homeostasis Elucidation mechanisms which pathogenesis may inform broader understanding role glial pathology disorders and, doing, enable new strategies glial-directed therapeutics.

Language: Английский

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Proteomic Analysis of Huntington’s Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets

Molecular & Cellular Proteomics, Journal Year: 2023, Volume and Issue: 22(5), P. 100534 - 100534

Published: March 22, 2023

Huntington's disease (HD) is a neurodegenerative caused by CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters function of HTT protein. Although expressed different tissues, medium-spiny projection neurons (MSNs) striatum are particularly vulnerable HD. Thus, we sought to define proteome human HD patient-derived MSNs. We differentiated HD72-induced pluripotent stem cells and isogenic controls into MSNs carried out quantitative proteomic analysis. Using data-dependent acquisitions with FAIMS for label-free quantification on Orbitrap Lumos mass spectrometer, identified 6323 proteins at least two unique peptides. Of these, 901 were altered significantly more HD72-MSNs than controls. Functional enrichment analysis upregulated demonstrated extracellular matrix DNA signaling (DNA replication pathway, double-strand break repair, G1/S transition) highest significance. Conversely, processes associated downregulated included neurogenesis-axogenesis, brain-derived neurotrophic factor-signaling Ephrin-A:EphA regulation synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, system major histocompatibility complex, lipid metabolism, cellular response stimulus. Moreover, involved formation maintenance axons, dendrites, synapses (e.g., septin protein members) dysregulated HD72-MSNs. Importantly, metabolism pathways altered, using image analysis, found that droplets accumulated HD72-MSN, suggesting deficit turnover lipids possibly through lipophagy. Our proteomics relevant confirm current new therapeutic targets

Language: Английский

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MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 4218 - 4218

Published: Feb. 20, 2023

DNA methylation, one of the most well-studied epigenetic modifications, is involved in a wide spectrum biological processes. Epigenetic mechanisms control cellular morphology and function. Such regulatory involve histone chromatin remodeling, non-coding RNA molecules, modifications. One modifications methylation that plays key roles development, health, disease. Our brain probably complex part our body, with high level methylation. A protein binds to different types methylated methyl-CpG binding 2 (MeCP2). MeCP2 acts dose-dependent manner its abnormally or low expression level, deregulation, and/or genetic mutations lead neurodevelopmental disorders aberrant Recently, some MeCP2-associated have emerged as neurometabolic disorders, suggesting role for metabolism. Of note, MECP2 loss-of-function mutation Rett Syndrome reported cause impairment glucose cholesterol metabolism human patients mouse models The purpose this review outline metabolic abnormalities currently no available cure. We aim provide an updated overview into defects associated MeCP2-mediated function consideration future therapeutic strategies.

Language: Английский

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Neurosteroid enantiomers as potentially novel neurotherapeutics

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105191 - 105191

Published: April 20, 2023

Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These modulate major signaling systems the brain intracellular processes including inflammation, cellular stress autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which physiochemically identical to their natural counterparts except rotation polarized light. led insights how NAS interact with receptors, ion channels sites action. Certain effects show high enantioselectivity, consistent actions chiral environments likely direct interactions proteins. Other no enantioselectivity even reverse enantioselectivity. The spectrum raises possibility that these agents, once considered only as tools preclinical studies, have potential complements some cases may exceed counterparts. Here review from perspective novel neurotherapeutics.

Language: Английский

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Neuronal and astrocytic contributions to Huntington’s disease dissected with zinc finger protein transcriptional repressors

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 111953 - 111953

Published: Jan. 1, 2023

Huntington's disease (HD) is caused by expanded CAG repeats in the huntingtin gene (HTT) resulting expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts, including striatal neurons and astrocytes. It unknown whether pathophysiology vivo can be attenuated lowering mHTT either cell type throughout brain, relative contributions astrocytes to HD remain undefined. We use zinc finger protein (ZFP) transcriptional repressors cell-selectively lower vivo. Astrocytes display loss essential functions such as cholesterol metabolism that are partly driven greater neuronal dysfunctions, which encompass neuromodulation, synaptic, intracellular signaling pathways. Using transcriptomics, proteomics, electrophysiology, behavior, we dissect astrocytic pathophysiology. Remarkably, brain-wide delivery ZFPs results strong lowering, rescue HD-associated behavioral molecular phenotypes, significant extension lifespan, findings support translational development.

Language: Английский

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Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures

Molecular Systems Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Abstract Huntington’s disease (HD) is a debilitating neurodegenerative disorder affecting an individual’s cognitive and motor abilities. HD caused by mutation in the huntingtin gene producing toxic polyglutamine-expanded protein (mHTT) leading to degeneration striatum cortex. Yet, molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect leveraging multi-epitope interaction assays, subcellular fractionation, thermal proteome profiling, genetic modifier assays. The use of human cell, mouse, fly models afforded capture distinct pools epitope-enriched tissue-dependent interactions linked dysregulated cellular pathways relevance. We established HTT association with nearly all subunits transcriptional regulatory Mediator complex (20/26), preferential enrichment MED15 tail domain. Using KO models, find modulates localization assembly Mediator. demonstrated striatal enriched functional regulators calcium homeostasis chromatin remodeling, whose relevance was supported modifiers Altogether, offer insights into tissue- localization-dependent (m)HTT functions pathobiology.

Language: Английский

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