Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study (original) (raw)
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Membrane organization and regulation of cellular Cholesterol homeostasis
An excess of intracellular free Cholesterol (Chol) is cytotoxic, and its homeostasis is crucial for cell viability. Apolipoprotein A-I (apoA-I) is a highly efficient Chol acceptor as it activates complex cellular pathways that tend to mobilize and export Chol from cellular depots. Here we hypothesize that membrane composition and/or organization is strongly involved in Chol homeostasis. To test this hypothesis, we constructed a cell line over expressing Stearoyl CoA desaturase (SCD-cells), which modifies plasma membrane (PM) composition by the enrichment of monounsaturated fatty,acids and determined this effect on membrane properties, cell viability and cholesterol homeostasis. PM in SCD-cells has a higher phospholipids/sphingomyelin ratio and is slightly enriched in Chol. These cells showed an increase in the cholesteryl esters/free Chol ratio, they were more resistant to Chol toxicity and in addition, they exported more caveolin than Control cells. The data suggest that cell functionality is preserved by regulating membrane fluidity and Chol exportation and storage.
Intracellular Cholesterol Trafficking and Impact in Neurodegeneration
Frontiers in molecular neuroscience, 2017
Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD), however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via s...
Plasmalogens the neglected regulatory and scavenging lipid species
Chemistry and Physics of Lipids, 2011
Plasmalogens are a class of phospholipids carrying a vinyl ether bond in sn-1 and an ester bond in sn-2 position of the glycerol backbone. Although they are widespread in all tissues and represent up to 18% of the total phospholipid mass in humans, their physiological function is still poorly understood. The aim of this review is to give an overview over the current knowledge in plasmalogen biology and pathology with an emphasis on neglected aspects of their involvement in neurological and metabolic diseases. Furthermore a better understanding of plasmalogen biology in health and disease could also lead to the development of better diagnostic and prognostic biomarkers for vascular and metabolic diseases such as obesity and diabetes mellitus, inflammation, neuro-degeneration and cancer.
Roles of Cholesterol and Lipids in the Etiopathogenesis of Alzheimer's Disease
Journal of Biomedicine and Biotechnology, 2006
Alzheimer's disease is the principal cause of dementia throughout the world and the fourth cause of death in developed economies.This brain disorder is characterized by the formation of brain protein aggregates, namely, the paired helical filaments and senile plaques. Oxidative stress during life, neuroinflamamtion, and alterations in neuron-glia interaction patterns have been also involved in the etiopathogenesis of this disease. In recent years, cumulative evidence has been gained on the involvement of alteration in neuronal lipoproteins activity, as well as on the role of cholesterol and other lipids in the pathogenesis of this neurodegenerative disorder. In this review, we analyze the links between changes in cholesterol homeostasis, and the changes of lipids of major importance for neuronal activity and Alheimer's disease. The investigation on the fine molecular mechanisms underlying the lipids influence in the etiopathogenesis of Alzheimer's disease may shed light into its treatment and medical management.
Aging Cell, 2011
Beta amyloid (bA) plays a central role in the pathogenesis of the most common and devastating neurodegenerative disorder, Alzheimer's disease (AD). The mechanisms of bA neurotoxicity remain controversial, but include dysregulation of calcium homeostasis and oxidative stress. A large body of data suggest that cholesterol plays a significant role in AD. In mixed cultures containing hippocampal neurons and astrocytes, we have shown that neurotoxic bA peptides (1-42 and 25-35) cause sporadic cytosolic calcium ([Ca 2+ ] c) signals in astrocytes but not in neurons, initiating a cascade that ends in neuronal death. We now show, using the cholesterol-sensitive fluorescent probe, Filipin, that membrane cholesterol is significantly higher in astrocytes than in neurons and mediates the selective response of astrocytes to bA. Thus, lowering [cholesterol] using mevastatin, methyl-b-cyclodextrin or filipin prevented the bA-induced [Ca 2+ ] c signals, while increased membrane [cholesterol] increased bA-induced [Ca 2+ ] c signals in both neurons and astrocytes. Addition of bA to lipid bilayers caused the appearance of a conductance that was significantly higher in membranes containing cholesterol. Increasing membrane [cholesterol] significantly increased bA-induced neuronal and astrocytic death. We conclude that a high membrane [cholesterol] promotes bA incorporation into membranes and increased [Ca 2+ ] c leading to cell death.
Brain Cholesterol: Long Secret Life Behind a Barrier
2010
Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450 -generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far. In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed. (Arterioscler Thromb Vasc Biol. 2004;24:806-815.)
Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis
eLife, 2014
When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the…
Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis
Molecular Neurobiology, 2013
Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid β (Aβ)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aβ-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aβ-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.
Brain cholesterol in normal and pathological aging
jle.com
Correct lipid homeostasis at the plasma membrane is essential for cell survival and performance. These are critically challenged in the aging brain. Changes in the levels of cholesterol, a major membrane component especially enriched in neurons, accompany the brain aging process. They also occur in neurodegenerative diseases. Understanding the causes and consequences of these changes is a crucial step when trying to delay the cognitive decline, which comes with age, or to design strategies to fight neurodegenerative disorders such as Alzheimer's disease. We here review work that has contributed to this understanding.