-
Nature Reviews. Molecular Cell Biology Apr 2020Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an... (Review)
Review
Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.
Topics: Animals; Cholesterol; Cholesterol Esters; Homeostasis; Humans; Lipid Metabolism; Lipoproteins
PubMed: 31848472
DOI: 10.1038/s41580-019-0190-7 -
Endocrine Practice : Official Journal... Dec 2020Cholesterol is an important molecule in humans and both its excess and its deficiency cause disease. Most clinicians appreciate its role in stabilizing cellular plasma... (Review)
Review
OBJECTIVE
Cholesterol is an important molecule in humans and both its excess and its deficiency cause disease. Most clinicians appreciate its role in stabilizing cellular plasma membranes but are unaware of its myriad other functions.
METHODS
This review highlights cholesterol's newly recognized important roles in human physiology and pathophysiology.
RESULTS
The basis for cholesterol's ubiquitous presence in eukaryote organisms is its three part structure involving hydrophilic, hydrophobic, and rigid domains. This structure permits cholesterol to regulate multiple cellular processes ranging from membrane fluidity and permeability to gene transcription. Cholesterol not only serves as a molecule of regulation itself, but also forms the backbone of all steroid hormones and vitamin D analogs. Cholesterol is responsible for growth and development throughout life and may be useful as an anticancer facilitator. Because humans have a limited ability to catabolize cholesterol, it readily accumulates in the body when an excess from the diet or a genetic abnormality occurs. This accumulation results in the foremost cause of death and disease (atherosclerosis) in the Western world. Identification of cholesterol's disease-producing capabilities dates back 5,000 years to the Tyrolean iceman and more recently to ancient mummies from many cultures throughout the world. In contrast, a deficiency of cholesterol in the circulation may result in an inability to distribute vitamins K and E to vital organs with serious consequences.
CONCLUSION
Understanding the benefits and hazards of cholesterol in the clinical setting will improve the endocrinologist's ability to control diseases associated with this unique molecule.
ABBREVIATIONS
CVD = cardiovascular disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NPC1L1 = Niemann-Pick C-1-like-1 protein; U.S. = United States; USDA = U.S. Department of Agriculture.
Topics: Atherosclerosis; Cholesterol; Cholesterol, HDL; Diet; Humans
PubMed: 33471744
DOI: 10.4158/EP-2020-0347 -
Frontiers in Bioscience (Landmark... Jan 2014Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in... (Review)
Review
Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in membranes, where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signaling functions. At an organismal level, cholesterol is the precursor for all steroid hormones, including gluco- and mineralo-corticoids, sex hormones and vitamin D, all of which regulate carbohydrate, sodium, reproductive and bone homeostasis, respectively. This sterol is also the precursor for bile acids, which are important for intestinal absorption of dietary lipids as well as energy and glucose metabolic regulation. Importantly, complex mechanisms maintain cholesterol within physiological ranges and the disregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these diseases has been demonstrated by diverse genetic and pharmacologic animal models that are commented in this review.
Topics: Atherosclerosis; Biological Transport; Cholesterol; Fetal Development; Humans
PubMed: 24389193
DOI: 10.2741/4216 -
Pharmacology & Therapeutics Sep 2023Neurodegeneration and its loss of cognitive function is associated with inflammation and an accumulation of lipids. In the periphery, cholesterol's uptake drives a major... (Review)
Review
Neurodegeneration and its loss of cognitive function is associated with inflammation and an accumulation of lipids. In the periphery, cholesterol's uptake drives a major component of chronic inflammation. In this perspective, we describe the cellular and molecular roles of cholesterol in neuroinflammation and contrast them with those in the periphery. Incorporating shared mechanisms from the periphery, cholesterol emerges as a central signal originating in astrocytes and connecting inflammatory escalation in neurons and microglia. A cholesterol uptake pathway is proposed for neuroinflammation, and we speculate on the binding of cholesterol transport protein apolipoprotein E (apoE), including the Christchurch mutant (R136S), to cell surface receptors as a potential protective modality against uptake of astrocyte cholesterol and escalated neuroinflammation. Lastly, we discuss the molecular basis of cholesterol signaling through nanoscopic clustering and peripheral sources of cholesterol after opening of the blood brain barrier.
Topics: Humans; Alzheimer Disease; Neuroinflammatory Diseases; Neurons; Cholesterol; Inflammation; Astrocytes
PubMed: 37390970
DOI: 10.1016/j.pharmthera.2023.108486 -
Journal of Molecular Endocrinology May 2018Cholesterol is an important regulator of cell signaling, both through direct impacts on cell membranes and through oxy-metabolites that activate specific receptors... (Review)
Review
Cholesterol is an important regulator of cell signaling, both through direct impacts on cell membranes and through oxy-metabolites that activate specific receptors (steroids, hydroxy-cholesterols, bile acids). Cholesterol moves slowly through and between cell membranes with the assistance of specific binding proteins and transfer processes. The prototype cholesterol regulator is the Steroidogenesis Acute Regulatory (STAR), which moves cholesterol into mitochondria, where steroid synthesis is initiated by cytochrome P450 11A1 in multiple endocrine cell types. CYP27A1 generates hydroxyl cholesterol metabolites that activate LXR nuclear receptors to control cholesterol homeostatic and transport mechanisms. LXR regulation of cholesterol transport and storage as cholesterol ester droplets is shared by both steroid-producing cells and macrophage. This cholesterol signaling is crucial to brain neuron regulation by astrocytes and microglial macrophage, mediated by ApoE and sensitive to disruption by β-amyloid plaques. sm-FISH delivers appreciable insights into signaling in single cells, by resolving single RNA molecules as mRNA and by quantifying pre-mRNA at gene loci. sm-FISH has been applied to problems in physiology, embryo development and cancer biology, where single cell features have critical impacts. sm-FISH identifies novel features of STAR transcription in adrenal and testis cells, including asymmetric expression at individual gene loci, delayed splicing and 1:1 association of mRNA with mitochondria. This may represent a functional unit for the translation-dependent cholesterol transfer directed by STAR, which integrates into mitochondrial fusion dynamics. Similar cholesterol dynamics repeat with different players in the cycling of cholesterol between astrocytes and neurons in the brain, which may be abnormal in neurodegenerative diseases.
Topics: Animals; Cells; Cholesterol; Humans; In Situ Hybridization, Fluorescence; Phosphoproteins; RNA Splicing; Signal Transduction
PubMed: 29691317
DOI: 10.1530/JME-17-0281 -
Chemistry and Physics of Lipids Sep 2016It is well known that cholesterol modifies the physical properties of lipid bilayers. For example, the much studied liquid-ordered Lo phase contains rapidly diffusing... (Review)
Review
It is well known that cholesterol modifies the physical properties of lipid bilayers. For example, the much studied liquid-ordered Lo phase contains rapidly diffusing lipids with their acyl chains in the all trans configuration, similar to gel phase bilayers. Moreover, the Lo phase is commonly associated with cholesterol-enriched lipid rafts, which are thought to serve as platforms for signaling proteins in the plasma membrane. Cholesterol's location in lipid bilayers has been studied extensively, and it has been shown - at least in some bilayers - to align differently from its canonical upright orientation, where its hydroxyl group is in the vicinity of the lipid-water interface. In this article we review recent works describing cholesterol's location in different model membrane systems with emphasis on results obtained from scattering, spectroscopic and molecular dynamics studies.
Topics: Cholesterol; Lipid Bilayers; Phospholipids
PubMed: 27056099
DOI: 10.1016/j.chemphyslip.2016.04.001 -
Klinische Wochenschrift Oct 1970
Review
Topics: Bile Acids and Salts; Cholesterol; Chylomicrons; Diet; Digestive System; Humans; Hydroxybutyrate Dehydrogenase; Hypercholesterolemia; Lipid Metabolism; Lipoproteins; Liver
PubMed: 4920502
DOI: 10.1007/BF01487127 -
Advances in Experimental Medicine and... 2019Cholesterol is a highly asymmetric lipid molecule. As an essential constituent of the cell membrane, cholesterol plays important structural and signaling roles in... (Review)
Review
Cholesterol is a highly asymmetric lipid molecule. As an essential constituent of the cell membrane, cholesterol plays important structural and signaling roles in various biological processes. The first high-resolution crystal structure of a transmembrane protein in complex with cholesterol was a human β-adrenergic receptor structure deposited to the Protein Data Bank in 2007. Since then, the number of the cholesterol-bound crystal structures has grown considerably providing an invaluable resource for obtaining insights into the structural characteristics of cholesterol binding. In this work, we examine the spatial and orientation distributions of cholesterol relative to the protein framework in a collection of 73 crystal structures of membrane proteins. To characterize the cholesterol-protein interactions, we apply singular value decomposition to an array of interatomic distances, which allows us to systematically assess the flexibility and variability of cholesterols in transmembrane proteins. Together, this joint analysis reveals the common characteristics among the observed cholesterol structures, thereby offering important guidelines for prediction and modification of potential cholesterol binding sites in transmembrane proteins.
Topics: Binding Sites; Cell Membrane; Cholesterol; Humans; Membrane Proteins; Protein Binding; Receptors, Adrenergic, beta-2
PubMed: 31098811
DOI: 10.1007/978-3-030-14265-0_4 -
Journal of Clinical Laboratory Analysis 1991Experimental evidence indicates a relationship between cholesterol alpha-epoxide and skin cancer, and exposure of skin fibroblasts to ultraviolet radiation enduces... (Review)
Review
Experimental evidence indicates a relationship between cholesterol alpha-epoxide and skin cancer, and exposure of skin fibroblasts to ultraviolet radiation enduces formation of significant levels of this oxide. Colon cancer is also etiologically linked to cholesterol oxidation products. Higher than normal levels of cholestanetriol have been found in patients with colon cancer and also in those with precancerous disorders such as adenomatous polyps and ulcerative colitis. Higher than normal levels of cholesterol alpha-epoxide have been found in breast fluid aspirates of women with benign breast disease, with or without atypical hyperplasia of the epithelium, and this may be a factor in the increased incidence of breast cancer associated with hyperplasia. Similarly, the observed increased levels of cholesterol alpha and beta-epoxides in prostatic fluid of men with benign prostatic hypertrophy may be associated with subsequent development of prostate cancer. Cholesterol alpha-epoxide has been found to be mutagenic to fibroblasts in culture and to induce morphological transformation in hamster embryo cells and in mouse C3H cells. 25-Hydroxycholesterol and 20 alpha-hydroxycholesterol are potent suppressors of generation and proliferation of tumor-specific cytotoxic T lymphocytes. Although investigations into the role of cholesterol oxidation products in cancer are still in the early stages, evidence to date indicates a potentially significant role in the induction of some types of cancer.
Topics: Animals; Biotransformation; Carcinogens; Cholesterol; Cholesterol, Dietary; Humans; Neoplasms; Neoplasms, Experimental
PubMed: 2061746
DOI: 10.1002/jcla.1860050312 -
Chemistry and Physics of Lipids Sep 2016The distribution of cholesterol between the two leaves of the plasma membrane in mammalian cells presents a conundrum; given cholesterol's known affinity for... (Review)
Review
The distribution of cholesterol between the two leaves of the plasma membrane in mammalian cells presents a conundrum; given cholesterol's known affinity for sphingomyelin, which resides predominantly in the exoplasmic leaf, why is it that experiment finds a majority of the cholesterol in the cytoplasmic leaf? This article reviews a recently proposed solution to this puzzle.
Topics: Animals; Biological Transport; Cell Membrane; Cholesterol
PubMed: 26724709
DOI: 10.1016/j.chemphyslip.2015.12.002