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Molecules (Basel, Switzerland) Apr 2013Cholesterol synthesis is a ubiquitous and housekeeping metabolic pathway that leads to cholesterol, an essential structural component of mammalian cell membranes,... (Review)
Review
Cholesterol synthesis is a ubiquitous and housekeeping metabolic pathway that leads to cholesterol, an essential structural component of mammalian cell membranes, required for proper membrane permeability and fluidity. The last part of the pathway involves steroidal triterpenes with cholestane ring structures. It starts by conversion of acyclic squalene into lanosterol, the first sterol intermediate of the pathway, followed by production of 20 structurally very similar steroidal triterpene molecules in over 11 complex enzyme reactions. Due to the structural similarities of sterol intermediates and the broad substrate specificity of the enzymes involved (especially sterol-Δ24-reductase; DHCR24) the exact sequence of the reactions between lanosterol and cholesterol remains undefined. This article reviews all hitherto known structures of post-squalene steroidal triterpenes of cholesterol synthesis, their biological roles and the enzymes responsible for their synthesis. Furthermore, it summarises kinetic parameters of enzymes (Vmax and Km) and sterol intermediate concentrations from various tissues. Due to the complexity of the post-squalene cholesterol synthesis pathway, future studies will require a comprehensive meta-analysis of the pathway to elucidate the exact reaction sequence in different tissues, physiological or disease conditions. A major reason for the standstill of detailed late cholesterol synthesis research was the lack of several steroidal triterpene standards. We aid to this efforts by summarizing commercial and laboratory standards, referring also to chemical syntheses of meiosis-activating sterols.
Topics: Animals; Cholesterol; Lanosterol; Metabolomics; Models, Animal; Squalene; Steroids; Sterols; Triterpenes
PubMed: 23558541
DOI: 10.3390/molecules18044002 -
Bioorganic & Medicinal Chemistry Aug 2022Intracellular sterol transport proteins (STPs) are crucial for maintaining cellular lipid homeostasis by regulating local sterol pools. Despite structural similarities... (Review)
Review
Intracellular sterol transport proteins (STPs) are crucial for maintaining cellular lipid homeostasis by regulating local sterol pools. Despite structural similarities in their sterol binding domains, STPs have different substrate specificities, intracellular localisation and biological functions. In this review, we highlight recent advances in the determination of STP structures and how this regulates their lipid specificities. Furthermore, we cover the important discoveries relating to the intracellular localisation of STPs, and the organelles between which lipid transport is carried out, giving rise to specific functions in health and disease. Finally, serendipitous and targeted efforts to identify small molecule modulators of STPs, as well as their ability to act as tool compounds and potential therapeutics, will be discussed.
Topics: Biological Transport; Carrier Proteins; Cell Membrane; Organelles; Sterols
PubMed: 35716590
DOI: 10.1016/j.bmc.2022.116856 -
Journal of Dairy Science Dec 2023Milk contains several components that are important for human nutrition and health. To date, studies on organic and conventional milk have focused on their gross...
Milk contains several components that are important for human nutrition and health. To date, studies on organic and conventional milk have focused on their gross composition and fatty acid content, but little attention has been paid to the differences between other minor components, such as sterols and vitamins that may have functional actions. The aim of this study was to investigate the nutritional differences among 3 types of milk from a dairy plant: conventional, high-quality, and organic (in compliance with European regulations) milk, focusing on minor components such as sterols of animal and plant origin (phytosterols), tocopherols, and bioactive fatty acids. Cholesterol ranged from 271.37 mg/100 g of fat in conventional milk to 278.76 mg/100 g of fat in organic milk. Lanosterol was the main minor animal sterol in cow milk (ranging from 3.41 to 4.37 mg/100 g of fat), followed by desmosterol. The amount of total plant sterols in the analyzed milk ranged from 4.43 mg/100 g of fat in organic to 4.71 mg/100 g of fat in high-quality milk. Brassicasterol was the main sterol of plant origin which varied from 2.6 mg/100 g of fat in conventional and organic milk, to 2.93 mg/100 g of fat in high-quality milk. The second most present phytosterol was β-sitosterol, which ranged from 0.86 mg/100 g of fat in conventional to 0.97 mg/100 g of fat in high-quality, and organic milk. The results of the study showed no significant differences in gross and sterol composition between the 3 types of milk. However, the only significant difference found was in the fatty acid profile, with a higher n-3 content found in high-quality milk than in conventional and organic milk. These findings suggest that the investigated product categories and labels have minimal effect on the sterol and fatty acid profile of commercial cow milk.
Topics: Humans; Animals; Female; Cattle; Sterols; Milk; Fatty Acids; Tocopherols; Phytosterols; Cholesterol; Vitamin E
PubMed: 37641300
DOI: 10.3168/jds.2023-23378 -
Cold Spring Harbor Perspectives in... May 2011Sterols and sphingolipids are considered mainly eukaryotic lipids even though both are present in some prokaryotes, with sphingolipids being more widespread than... (Review)
Review
Sterols and sphingolipids are considered mainly eukaryotic lipids even though both are present in some prokaryotes, with sphingolipids being more widespread than sterols. Both sterols and sphingolipids differ in their structural features in vertebrates, plants, and fungi. Interestingly, some invertebrates cannot synthesize sterols de novo and seem to have a reduced dependence on sterols. Sphingolipids and sterols are found in the plasma membrane, but we do not have a clear picture of their precise intracellular localization. Advances in lipidomics and subcellular fractionation should help to improve this situation. Genetic approaches have provided insights into the diversity of sterol and sphingolipid functions in eukaryotes providing evidence that these two lipid classes function together. Intermediates in sphingolipid biosynthesis and degradation are involved in signaling pathways, whereas sterol structures are converted to hormones. Both lipids have been implicated in regulating membrane trafficking.
Topics: Animals; Cell Fractionation; Cell Membrane; Models, Biological; Signal Transduction; Sphingolipids; Sterols
PubMed: 21454248
DOI: 10.1101/cshperspect.a004762 -
Annual Review of Cell and Developmental... Oct 2017In eukaryotes, the synthesis and uptake of sterols undergo stringent multivalent regulation. Both individual enzymes and transcriptional networks are controlled to meet... (Review)
Review
In eukaryotes, the synthesis and uptake of sterols undergo stringent multivalent regulation. Both individual enzymes and transcriptional networks are controlled to meet changing needs of the many sterol pathway products. Regulation is tailored by evolution to match regulatory constraints, which can be very different in distinct species. Nevertheless, a broadly conserved feature of many aspects of sterol regulation is employment of proteostasis mechanisms to bring about control of individual proteins. Proteostasis is the set of processes that maintain homeostasis of a dynamic proteome. Proteostasis includes protein quality control pathways for the detection, and then the correction or destruction, of the many misfolded proteins that arise as an unavoidable feature of protein-based life. Protein quality control displays not only the remarkable breadth needed to manage the wide variety of client molecules, but also extreme specificity toward the misfolded variants of a given protein. These features are amenable to evolutionary usurpation as a means to regulate proteins, and this approach has been used in sterol regulation. We describe both well-trod and less familiar versions of the interface between proteostasis and sterol regulation and suggest some underlying ideas with broad biological and clinical applicability.
Topics: Animals; Endoplasmic Reticulum-Associated Degradation; Humans; Lipid Metabolism; Proteostasis; Signal Transduction; Sterol Regulatory Element Binding Proteins; Sterols
PubMed: 28992438
DOI: 10.1146/annurev-cellbio-111315-125036 -
Trends in Biochemical Sciences Feb 2017Sterol transport between the endoplasmic reticulum (ER) and plasma membrane (PM) occurs by nonvesicular mechanisms requiring sterol transport proteins (STPs). Here we... (Review)
Review
Sterol transport between the endoplasmic reticulum (ER) and plasma membrane (PM) occurs by nonvesicular mechanisms requiring sterol transport proteins (STPs). Here we examine the idea that transport is enhanced at membrane contact sites where the ER is closely apposed to the PM. We conclude that sterol desorption from the membrane, rather than STP-mediated diffusion, is rate limiting in the cellular context, so there is no apparent kinetic benefit to having STP-mediated sterol transfer occur at contact sites. Contact sites may instead compartmentalize lipid synthesis or transport machinery, providing opportunities for regulation.
Topics: Animals; Biological Transport; Cell Membrane; Endoplasmic Reticulum; Humans; Sterols
PubMed: 27956059
DOI: 10.1016/j.tibs.2016.11.004 -
Biochimica Et Biophysica Acta Jul 2009We review the cellular mechanisms implicated in cholesterol trafficking and distribution. Recent studies have provided new information about the distribution of sterols... (Review)
Review
We review the cellular mechanisms implicated in cholesterol trafficking and distribution. Recent studies have provided new information about the distribution of sterols within cells, including analysis of its transbilayer distribution. The cholesterol interaction with other lipids and its engagement in various trafficking processes will determine its proper level in a specific membrane; making the cholesterol distribution uneven among the various intracellular organelles. The cholesterol content is important since cholesterol plays an essential role in membranes by controlling their physicochemical properties as well as key cellular events such as signal transduction and protein trafficking. Cholesterol movement between cellular organelles is highly dynamic, and can be achieved by vesicular and non-vesicular processes. Various studies have analyzed the proteins that play a significant role in these processes, giving us new information about the relative importance of these two trafficking pathways in cholesterol transport. Although still poorly characterized in many trafficking routes, several potential sterol transport proteins have been described in detail; as a result, molecular mechanisms for sterol transport among membranes start to be appreciated.
Topics: Biological Transport; Cholesterol; Intracellular Fluid; Lipid Bilayers; Phospholipids; Sterols
PubMed: 19286471
DOI: 10.1016/j.bbalip.2009.03.002 -
Annual Review of Cell and Developmental... 2010Oxysterol-binding protein (OSBP)-related proteins (ORPs) are lipid-binding proteins that are conserved from yeast to humans. They are implicated in many cellular... (Review)
Review
Oxysterol-binding protein (OSBP)-related proteins (ORPs) are lipid-binding proteins that are conserved from yeast to humans. They are implicated in many cellular processes including signaling, vesicular trafficking, lipid metabolism, and nonvesicular sterol transport. All ORPs contain an OSBP-related domain (ORD) that has a hydrophobic pocket that binds a single sterol. ORDs also contain additional membrane-binding surfaces, some of which bind phosphoinositides and may regulate sterol binding. Studies in yeast suggest that ORPs function as sterol transporters, perhaps in regions where organelle membranes are closely apposed. Yeast ORPs also participate in vesicular trafficking, although their role is unclear. In mammalian cells, some ORPs function as sterol sensors that regulate the assembly of protein complexes in response to changes in cholesterol levels. This review will summarize recent advances in our understanding of how ORPs bind lipids and membranes and how they function in diverse cellular processes.
Topics: Animals; Carrier Proteins; Humans; Lipid Metabolism; Membranes; Sterols
PubMed: 19575662
DOI: 10.1146/annurev.cellbio.042308.113334 -
The Journal of Steroid Biochemistry and... May 2017Dietary sterols are nutritionally interesting compounds which can suffer oxidation reactions. In the case of plant sterols, they are being widely used for food... (Review)
Review
Dietary sterols are nutritionally interesting compounds which can suffer oxidation reactions. In the case of plant sterols, they are being widely used for food enrichment due to their hypocholesterolemic properties. Besides, cholesterol and plant sterols oxidation products are associated with the development of cardiovascular and neurodegenerative diseases, among others. Therefore, the evaluation of the particular factors affecting sterol degradation and oxysterols formation in foods is of major importance. The present work summarizes the main results obtained in experiments which aimed to study four aspects in this context: the effect of the heating treatment, the unsaturation degree of the surrounding lipids, the presence of antioxidants on sterols degradation, and at last, oxides formation. The use of model systems allowed the isolation of some of these effects resulting in more accurate data. Thus, these results could be applied in real conditions.
Topics: Animals; Antioxidants; Cholesterol; Hot Temperature; Humans; Kinetics; Models, Theoretical; Oxygen; Oxysterols; Phytosterols; Sitosterols; Stigmasterol
PubMed: 26921766
DOI: 10.1016/j.jsbmb.2016.02.027 -
Annual Review of Biochemistry 2011Sterol metabolites are critical signaling molecules that regulate metabolism, development, and homeostasis. Oxysterols, bile acids (BAs), and steroids work primarily... (Review)
Review
Sterol metabolites are critical signaling molecules that regulate metabolism, development, and homeostasis. Oxysterols, bile acids (BAs), and steroids work primarily through cognate sterol-responsive nuclear hormone receptors to control these processes through feed-forward and feedback mechanisms. These signaling pathways are conserved from simple invertebrates to mammals. Indeed, results from various model organisms have yielded fundamental insights into cholesterol and BA homeostasis, lipid and glucose metabolism, protective mechanisms, tissue differentiation, development, reproduction, and even aging. Here, we review how sterols act through evolutionarily ancient mechanisms to control these processes.
Topics: Animals; Energy Metabolism; Evolution, Molecular; Fasting; Glucose; Growth and Development; Homeostasis; Humans; Immunity; Life Expectancy; Lipid Metabolism; Liver X Receptors; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Sterols
PubMed: 21495846
DOI: 10.1146/annurev-biochem-081308-165917