Reproduced from ref. Finally, the side chain of cholesterol is saturated and relatively unsubstituted with extra methyl groups, resulting in a hydrophobic structure that is usually linear and aligned with the plane of the steroid nucleus Figure 2 a. This design allows optimal van der Waals interactions with phospholipid fatty acyl groups while avoiding disruption of the bilayer 1 , 7.
Interestingly, plants evolved a different series of enzymatic reactions in which squalene is converted to cycloartenol instead of lanosterol, followed by further modifications that result in the synthesis of phytosterols Figure 1. These bulky side chains, which are often aligned out of the plane of the steroid nucleus, alter critical properties of the membranes of higher animal cells 9.
Indeed, higher animals have evolved specific, energy-requiring molecules to excrete such sterols following intestinal absorption Plant cell plasma membranes, however, encounter a much higher proton gradient than most animal cell plasma membranes, and the bulky side chains of phytosterols appear to be optimally designed to prevent proton leaks, thus saving the cells a great expenditure of metabolic energy 4.
The result of the molecular evolution of cholesterol is an exquisitely designed molecule that can influence many important properties of the vertebrate plasma membrane.
MATHEMATICAL MODEL OF CHOLESTEROL BIOSYNTHESIS REGULATION IN THE CELL
In addition to generally affecting membrane permeability and integral membrane protein function, cholesterol-induced membrane packing in lateral microdomains, or rafts, of the plasma membrane can provide a scaffold for a variety of membrane-associated signaling proteins, as reviewed by Simons and Ehehalt 11 in this Perspective series. As such, the role of cholesterol in the proper functioning of oncogenic G proteins 12 , proteases of amyloid precursor protein 13 , and signaling proteins critical for sperm activation Travis and Kopf , this series extends the biomedical implications of cholesterol from cancer to Alzheimer disease to reproductive biology.
Moreover, recent work has revealed a critical role for cholesterol in glial cell—mediated synaptogenesis, perhaps by directly affecting the structures of synaptic vesicles and postsynaptic membranes or by activating a neuronal signaling pathway Cholesterol can also influence the localization of a protein important in vertebrate development, Sonic hedgehog, by covalently attaching to the protein itself Jeong and McMahon , this series.
The formation of cholesterol-rich microdomains in the plasma membrane is also critical for the budding of clathrin-coated pits 17 , a key step in receptor-mediated endocytosis. The influence of cholesterol on normal cellular physiology is clearly demonstrated by what happens when cells are experimentally depleted of cholesterol or when, by accidents of nature, mutations prevent the proper synthesis or trafficking of cholesterol. The critical membrane-organizing functions of cholesterol justify the evolution of an elaborate feedback regulatory system.
As described by Horton, Goldstein, and Brown in a recent Spotlight in the JCI 21 , sterol starvation induces the translocation of SREBP-SCAP complex to the Golgi apparatus, where two proteolytic cleavages generate a transcriptional activator that induces genes controlling both cholesterol biosynthesis and exogenous cholesterol uptake. Interestingly, insect cells have all of the components of this regulatory system, yet they do not synthesize cholesterol, and their ability to process SREBP is not affected by exogenous sterols. Rather, the system is used in phosphatidylethanolamine-mediated feedback regulation of the biosynthesis of fatty acids and phospholipids, which critically affect membrane structure in these cells Because phatidylethanolamine and cholesterol share the ability to alter membrane structure and thus to alter SCAP conformation and SREBP processing 22 , vertebrate evolution appears to have usurped a pre-existing system that was devoted to membrane lipid homeostasis even before cholesterol emerged as the key molecular organizer of cell membranes.
Functions of cholesterol metabolites and immediate biosynthetic precursors of cholesterol. As if the membrane effects of cholesterol were not enough, nature has used the cholesterol backbone as a precursor for a variety of biologically active molecules Figures 3 and 4. In one pathway, at least 14 different liver enzymes add polarity to the ring structure and side chain of cholesterol to create ideal micellar solubilization agents for the absorption of dietary fats and fat-soluble vitamins Importantly, bile acids and thus cholesterol are conserved during the process of lipid absorption through the enterohepatic circulation.
Thus, by facilitating cholesterol absorption, bile acids ensure adequate supplies of total body cholesterol when this critical lipid is in short supply. However, pharmacologic interruption of the enterohepatic circulation of bile acids leads to increased conversion of hepatic cholesterol into bile acids, thus converting the bile acid pathway into one that can actually help eliminate excess body cholesterol Biosynthesis of cholesterol-derived hormones. In an interesting twist of evolution, the liver of the spermiating adult male sea lamprey, an ancestral jawless fish, synthesizes a sulfated bile acid 26 Figure 4.
However, these fish have neither bile ducts nor gall bladders, and they do not feed while spermiating. Rather, the bile acid is transported to the gills, where specialized glands secrete the substance into surrounding waters. There, it functions as an ideal long-distance pheromone to attract females to nests built by the males Work in vitro has demonstrated that cholesterol modified by the addition of one additional hydroxyl group on the side chain creates a molecule that is able to activate a nuclear hormone receptor called LXR Thus, it is possible that specific side-chain hydroxylases play a critical role in so-called reverse cholesterol transport.
Another scenario involves the oxidative cleavage of the side chain of cholesterol to a C20 ketone moiety Figure 3. This reaction is catalyzed by a specific cytochrome P enzyme in the mitochondria of steroidogenic cells see Jefcoate , this series and possibly brain cells.
How it’s made: Cholesterol production in your body
In other cases, the side chain is oxidatively cleaved further to yield a C17 hydroxyl group e. Different degrees of ring demethylations, oxidations, and reductions add further variety to the shape of the steroid nucleus and thus confer their specificity for individual hormone receptors In the classic pathway defined for steroid hormone signaling, the hormone-receptor complex enters the nucleus and transcriptionally activates genes critically involved in reproductive biology e.
An evolutionary preview of this paradigm is found in insects, where exogenously derived sterols are oxidized to form ecdysteroids Figure 4 , which control metamorphosis by interacting with nuclear hormone receptors Interestingly, recent data have suggested that the activation of estrogen and androgen receptors by sex hormones can lead to nongenotropic effects in cells, such as attenuation of apoptosis Similarly, certain neurosteroids can directly modulate the activity of GABA receptors in the brain 32 Figure 4.
Finally, nature has also taken advantage of some of the immediate precursors of cholesterol to fulfill other critical functions. For example, 7-dehydrocholesterol in the skin is converted to cholecalciferol vitamin D3 via cleavage of the B ring by near ultraviolet irradiation 33 Figure 3. A similar reaction occurs in plants, where ergosterol is converted to ergocalciferol vitamin D2. Further hydroxylations at the C25 and C1 positions lead to the hormonally active molecule 1,dihydroxy-vitamin D, which interacts with a nuclear hormone receptor that critically affects body calcium metabolism Likewise, lanosterol-derived molecules called meiosis-activating sterols are employed by mammals to activate resumption of meiosis in oocytes and spermatozoa 34 Figure 4.
In summary, by oxidative cyclization and demethylation of an acetate-derived hydrophobic molecule, nature has created an amphipathic planar structure that, directly or through modifications, affects an incredible array of critical biological processes. These processes affect cellular membrane physiology, dietary nutrient absorption, reproductive biology, stress responses, salt and water balance, and calcium metabolism.
Each of these processes is absolutely necessary for organisms to reach reproductive age. Thus, there has been strong evolutionary pressure to ensure that the body in general and individual cells in particular have an adequate supply of cholesterol. Indeed, the regulatory response of cells to sterol starvation, as mentioned above, is exquisitely designed for this purpose. These regulatory processes can also protect cells from moderate degrees of cholesterol excess.
The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells
What nature did not plan for, however, was how to handle levels of cholesterol that exceed these limits. Homo sapiens has many physical characteristics of a vegetarian organism e. As such, intestinal and hepatic lipid metabolism likely evolved to convert whatever dietary fats were available into a form, namely, triglyceride-rich lipoproteins, that could supply energy to tissues. Indeed, the way cells ensure proper levels of endogenous cholesterol synthesis when exogenous sources are low is part of the exquisite story of cellular regulation that was described recently in the JCI by Horton, Goldstein, and Brown Those cells that use cholesterol as a precursor to other molecules, such as steroidogenic cells steroid hormones and hepatocytes bile acids , may need an exogenous supply under certain conditions, but this could easily be met by the internalization of the small amount of cholesterol left in the remnants of triglyceride-rich lipoproteins or in the LDL-like and HDL-like by-products of triglyceride-rich lipoprotein metabolism.
Intruding on this serene picture of metabolic harmony was the development of the superior intellect of modern humans, which enabled our species to secure the higher energy content of animal-derived foods at a much lower cost to metabolic energy. For reasons that are still not clear, the ingestion of saturated fats often causes a dramatic rise in plasma cholesterol levels, including those in remnant lipoproteins and LDL.
The increase in plasma cholesterol is further exacerbated by obesity, insulin resistance, and perturbations of glucose and fatty acid metabolism, all of which accompany sedentary lifestyles. Even with these problems, the degree of plasma cholesterol elevation that occurs at or before reproductive age usually poses no immediate threat. For cells that internalize some of this excess cholesterol, there are multiple protective mechanisms, including downregulation of endogenous cholesterol biosynthesis and of LDL receptors, intracellular esterification of the excess cholesterol by acyl-coenzyme A:cholesterol acyltransferase, and efflux of cholesterol by multiple pathways For tissues, the adverse reactions that occur in response to the accumulation of large amounts of extracellular cholesterol-rich lipoproteins take years to develop.
In post-reproductive life, however, the pressures of evolution have little impact, and the toll for elevated cholesterol is eventually paid. Clearly, the highest toll is associated with atherosclerotic vascular disease, although other consequences of persistently elevated body cholesterol include cholesterol gallstones, liver dysfunction, cholesterol crystal emboli, and dermatological abnormalities e.
In the case of vascular disease, the persistently high levels of circulating cholesterol-rich lipoproteins lead gradually but inexorably to their accrual in the subendothelial space of certain segments of midsize and small arteries 38 Figure 5. Thus, macrophages, T cells, and their inflammatory cytokines enter the affected areas of the arterial wall in response to excess cholesterol-rich lipoproteins, but what they encounter is no ordinary bacteria or virus.
Rather, cellular reactions to cholesterol, products of cholesterol oxidation, and other lipids that are packaged with cholesterol-carrying lipoproteins e. Free cholesterol and certain oxidized forms of cholesterol are particularly toxic to lesional cells, and death of lesional macrophages exposed to excess free cholesterol or oxysterols is likely an important cause of lesional necrosis ref.
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If you have previously obtained access with your personal account, Please log in. If you previously purchased this article, Log in to Readcube. Log out of Readcube. Click on an option below to access. Log out of ReadCube. Parenchyma proliferation is accompanied by a peculiar modification of the cholesterol metabolism involving both the growing tissue and the plasma compartment.
The increase of cholesterol synthesis and uptake has been largely described in the literature and mainly ascribed to the increased requirement of cholesterol for new membrane biogenesis.
The dramatic reduction of cholesterol efflux, which probably contributes to the increase of cholesterol esterification and accumulation, has also been largely described, although, further to acting as a prompt pool for membrane biogenesis requirements, its significance and possible influence on cholesterol homeostasis during growth has been almost completely neglected.
In this short review, the most widely known modifications and new insights into the cholesterol metabolism during the growth of normal and tumoral cells will be discussed. Particular attention will be paid to the most widely known modifications of cholesterol storage and efflux. The possible implication of proteins in membrane cholesterol translocation causing cholesterol to be directed towards the ER for esterification by ACAT rather than being released by the appropriate external acceptor, i. HDL, during proliferation will be discussed. Volume , Issue 8. The full text of this article hosted at iucr.
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