Cholesterol functions as the primary sterol in all animal organisms, exhibiting widespread distribution across bodily tissues, particularly within the brain and spinal cord, as well as in various animal fats and oils.
Cholesterol is the principal sterol of all animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.
Every animal cell synthesizes cholesterol, which is a vital structural and signaling constituent of their cell membranes. Vertebrate hepatic cells are generally responsible for the highest production levels. Within the brain, astrocytes generate cholesterol and facilitate its delivery to neurons. Prokaryotic organisms, including bacteria and archaea, typically lack cholesterol, with notable exceptions like Mycoplasma, which necessitates cholesterol for proliferation. Furthermore, cholesterol acts as a precursor molecule for the synthesis of steroid hormones, bile acids, and vitamin D.
Elevated concentrations of circulating cholesterol, particularly when associated with low-density lipoprotein (LDL), commonly termed "bad cholesterol," are correlated with an increased susceptibility to cardiovascular pathologies.
The initial identification of cholesterol in its solid state occurred in gallstones in 1769 by François Poulletier de la Salle. Subsequently, in 1815, the chemist Michel Eugène Chevreul assigned the compound the designation "cholesterine."
Etymological Origins
The term cholesterol derives from the Ancient Greek components chole-, signifying 'bile', and stereos, meaning 'solid', augmented by the chemical suffix -ol, which denotes an alcohol.
Physiological Role
Cholesterol is indispensable for the sustenance of all animal life. Although most cells possess the capacity for its synthesis, the predominant portion of cholesterol is either consumed exogenously or produced by hepatocytes, subsequently transported via the bloodstream to peripheral cells. The concentrations of cholesterol within peripheral tissues are regulated by an equilibrium between cellular absorption and efflux. Typically, cerebral cholesterol operates independently from peripheral cholesterol, meaning dietary and hepatically synthesized cholesterol do not traverse the blood-brain barrier. Instead, astrocytes are responsible for the production and distribution of cholesterol within the brain.
De novo cholesterol synthesis, occurring in both astrocytes and hepatocytes, involves an intricate 37-step biochemical pathway. This process initiates with the mevalonate or HMG-CoA reductase pathway, which is the pharmacological target of statin medications and comprises the initial 18 steps. Subsequently, 19 further steps are required to transform the intermediate lanosterol into cholesterol. An average human male, weighing approximately 68 kg (150 lb), typically synthesizes around 1 gram (1,000 mg) of cholesterol daily, with the body containing approximately 35 g, primarily localized within cellular membranes.
The typical daily dietary intake of cholesterol for a male in the United States averages 307 mg. The majority of consumed cholesterol is esterified, leading to its limited absorption within the gastrointestinal tract. The organism also counteracts the absorption of dietary cholesterol by downregulating its endogenous cholesterol synthesis. Consequently, dietary cholesterol exhibits minimal, if any, impact on circulating cholesterol concentrations seven to ten hours post-ingestion. In contrast, studies in rats demonstrate an inverse relationship between cholesterol consumption and blood cholesterol levels: higher dietary cholesterol intake correlates with lower blood cholesterol. However, during the initial seven hours following cholesterol ingestion, as absorbed lipids are disseminated throughout the extracellular fluid by various lipoproteins, a transient increase in concentrations is observed.
Plants synthesize cholesterol in negligible quantities. They predominantly produce phytosterols, which are structurally analogous compounds that competitively inhibit cholesterol reabsorption within the intestinal lumen, thereby potentially mitigating overall cholesterol absorption. Upon absorbing phytosterols instead of cholesterol, intestinal epithelial cells typically efflux these phytosterol molecules back into the gastrointestinal tract, representing a crucial protective mechanism. The daily intake of naturally occurring phytosterols, encompassing both plant sterols and stanols, typically varies between approximately 200–300 mg, contingent upon dietary patterns. Specialized experimental vegetarian diets have been formulated to achieve intakes exceeding 700 mg per day.
Functional Significance
Cellular Membranes
Cholesterol is ubiquitously found in varying concentrations within all animal cell membranes, yet it is entirely absent in prokaryotic organisms. This lipid is essential for membrane construction and maintenance, actively regulating membrane fluidity across physiological temperature ranges. Each cholesterol molecule features a hydroxyl group that engages with surrounding water molecules, mirroring the interaction of polar heads from membrane phospholipids and sphingolipids. Concurrently, its substantial steroid nucleus and hydrocarbon chain are embedded within the membrane, positioned adjacent to the nonpolar fatty-acid chains of other lipids. This interaction with phospholipid fatty-acid chains enhances membrane packing, thereby modifying membrane fluidity and preserving structural integrity. Consequently, animal cells are not necessitated to construct cell walls, unlike plant cells and most bacteria. The resulting membrane exhibits stability and durability without compromising flexibility, which facilitates shape alterations in animal cells and enables animal locomotion.
The tetracyclic ring structure of cholesterol influences cell membrane fluidity; its trans conformation renders the molecule, excluding its side chain, rigid and planar. Beyond its structural contributions, cholesterol additionally diminishes the plasma membrane's permeability to neutral solutes, hydrogen ions, and sodium ions.
Substrate presentation
Cholesterol plays a regulatory role in the biological process of substrate presentation and in the activation mechanisms of enzymes that utilize this process. Phospholipase D2 (PLD2) serves as a prominent illustration of an enzyme whose activation relies on substrate presentation. Palmitoylation directs PLD2 to cholesterol-dependent lipid domains, frequently referred to as "lipid rafts." Phosphatidylcholine (PC), the substrate for phospholipase D, is an unsaturated lipid found in low concentrations within lipid rafts. Conversely, PC localizes to the disordered regions of the cell membrane, co-localizing with the polyunsaturated lipid phosphatidylinositol 4,5-bisphosphate (PIP2). PLD2 possesses a specific PIP2 binding domain. An elevation in membrane PIP2 concentration prompts PLD2 to dissociate from cholesterol-dependent domains and bind to PIP2. This binding event subsequently grants PLD2 access to its substrate, PC, thereby initiating catalysis via substrate presentation.
Signaling
Cholesterol participates in cellular signaling pathways by facilitating the formation of lipid rafts within the plasma membrane. These rafts serve to cluster receptor proteins, bringing them into close proximity with elevated concentrations of second messenger molecules. Furthermore, in multi-layered structures, cholesterol and phospholipids, both acting as electrical insulators, can enhance the velocity of electrical impulse transmission along nerve tissue. Many neuronal fibers are enveloped by a myelin sheath, which is notably rich in cholesterol due to its derivation from compacted layers of Schwann cell or oligodendrocyte membranes. This sheath provides crucial insulation, enabling more efficient impulse conduction. Demyelination, defined as the loss of myelin, is considered a contributing factor to the pathogenesis of multiple sclerosis.
Cholesterol interacts with and modulates the gating mechanisms of various ion channels, including the nicotinic acetylcholine receptor, the GABAA receptor, and the inward-rectifier potassium channel. Moreover, cholesterol activates the estrogen-related receptor alpha (ERRα) and is potentially its endogenous ligand. The receptor's constitutive activity might be attributable to cholesterol's ubiquitous presence throughout the body. The suppression of ERRα signaling, achieved through reduced cholesterol production, has been recognized as a crucial mediator of the effects exerted by statins and bisphosphonates on bone, muscle, and macrophages. Consequently, these findings have led to the proposition that ERRα should be reclassified from an orphan receptor to a cholesterol receptor.
As a chemical precursor
Intracellularly, cholesterol functions as a precursor molecule for numerous biochemical pathways. For instance, it is indispensable for the biosynthesis of vitamin D, involved in calcium metabolism, and for all steroid hormones. This includes adrenal gland hormones such as cortisol and aldosterone, as well as sex hormones like progesterone, estrogens, and testosterone, along with their respective derivatives.
Epidermis
The stratum corneum, the outermost epidermal layer, consists of terminally differentiated, enucleated corneocytes embedded within a lipid matrix, often likened to "bricks and mortar." Cholesterol, alongside ceramides and free fatty acids, constitutes this lipid mortar, forming a water-impermeable barrier that effectively prevents evaporative water loss. Generally, the epidermal lipid matrix comprises an equimolar blend of ceramides (approximately 50% by weight), cholesterol (approximately 25% by weight), and free fatty acids (approximately 15% by weight), with minor proportions of other lipids also present. Cholesterol sulfate achieves its peak concentration within the granular layer of the epidermis. Subsequently, steroid sulfate sulfatase reduces its concentration in the stratum corneum. The epidermal concentration of cholesterol sulfate exhibits variability across different anatomical locations, with the lowest levels observed in the heel of the foot.
Metabolism
Cholesterol undergoes a recycling process within the body. The liver secretes cholesterol into biliary fluids, which are subsequently stored in the gallbladder before being excreted in a non-esterified form (via bile) into the digestive tract. Approximately 50% of this excreted cholesterol is typically reabsorbed into the bloodstream by the small intestine.
Biosynthesis and Regulation
Biosynthesis
Virtually all animal tissues synthesize cholesterol from acetyl-CoA. All animal cells, with limited exceptions among invertebrates, produce cholesterol for both membrane structural integrity and other physiological functions, exhibiting varying production rates dependent on cell type and organ function. Approximately 80% of the total daily cholesterol synthesis occurs in the liver and intestines; other significant sites of synthesis include the brain, adrenal glands, and reproductive organs.
Cholesterol synthesis within the body commences with the mevalonate pathway, in which two molecules of acetyl-CoA undergo condensation to yield acetoacetyl-CoA. Subsequently, a second condensation reaction occurs between acetyl-CoA and acetoacetyl-CoA, forming 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).
Subsequently, this molecule is reduced to mevalonate by the enzyme HMG-CoA reductase. The formation of mevalonate represents the rate-limiting and irreversible step in cholesterol synthesis and serves as the primary target for statins, a class of cholesterol-lowering medications.
Mevalonate is ultimately converted to isopentenyl pyrophosphate (IPP) via two phosphorylation steps and a single decarboxylation step, all requiring ATP.
Three molecules of isopentenyl pyrophosphate undergo condensation to produce farnesyl pyrophosphate, a reaction catalyzed by geranyl transferase.
Subsequently, two molecules of farnesyl pyrophosphate condense to yield squalene, a process mediated by squalene synthase within the endoplasmic reticulum.
Oxidosqualene cyclase subsequently cyclizes squalene, leading to the formation of lanosterol.
Ultimately, lanosterol is transformed into cholesterol through one of two distinct pathways: the Bloch pathway or the Kandutsch-Russell pathway. The subsequent 19 steps leading to cholesterol involve the participation of NADPH and oxygen for the oxidation and removal of methyl groups, mutases for the rearrangement of alkene groups, and NADH for the reduction of ketones.
Konrad Bloch and Feodor Lynen were jointly awarded the Nobel Prize in Physiology or Medicine in 1964 for their elucidation of mechanisms and regulatory aspects of cholesterol and fatty acid metabolism.
Regulation of Cholesterol Synthesis
Cholesterol biosynthesis is directly modulated by prevailing cholesterol concentrations, although the precise homeostatic mechanisms remain incompletely elucidated. Elevated dietary intake results in a net reduction in endogenous synthesis, while diminished intake produces the inverse outcome. The primary regulatory mechanism involves the detection of intracellular cholesterol within the endoplasmic reticulum by the sterol regulatory element-binding protein (SREBP 1 and 2). When cholesterol is abundant, SREBP forms a complex with two other proteins: SREBP cleavage-activating protein (SCAP) and INSIG-1. A decline in cholesterol levels triggers the dissociation of INSIG-1 from the SREBP-SCAP complex, enabling the complex to translocate to the Golgi apparatus. Within the Golgi, SREBP undergoes proteolytic cleavage by site-1 protease (S1P) and site-2 protease (S2P), enzymes activated by SCAP in response to low cholesterol concentrations.
The cleaved SREBP subsequently translocates to the nucleus, where it functions as a transcription factor, binding to the sterol regulatory element (SRE) to stimulate the transcription of numerous genes. These genes include those encoding the low-density lipoprotein (LDL) receptor and HMG-CoA reductase. The LDL receptor is responsible for scavenging circulating LDL from the bloodstream, while HMG-CoA reductase promotes an increase in endogenous cholesterol production. A significant portion of this signaling pathway was elucidated by Dr. Michael S. Brown and Dr. Joseph L. Goldstein during the 1970s. Their pioneering work earned them the Nobel Prize in Physiology or Medicine in 1985. Subsequent research by these scientists has demonstrated how the SREBP pathway regulates the expression of many genes involved in lipid formation, metabolism, and the allocation of bodily fuels.
Cholesterol synthesis can be inhibited when cholesterol concentrations are elevated. HMG-CoA reductase possesses both a cytosolic domain, which is responsible for its catalytic activity, and a membrane domain that detects signals for its degradation. Elevated concentrations of cholesterol and other sterols induce a conformational change in the oligomerization state of this membrane domain, rendering the enzyme more susceptible to proteasomal destruction. Furthermore, the activity of HMG-CoA reductase can be diminished through phosphorylation by an AMP-activated protein kinase. Since this kinase is activated by AMP, a product of ATP hydrolysis, it logically follows that cholesterol synthesis is suppressed when cellular ATP levels are low.
Plasma Transport and Absorption Regulation
As an isolated molecule, cholesterol exhibits minimal solubility in water, classifying it as hydrophilic. Consequently, its concentration in blood plasma is exceedingly low. For efficient transport, cholesterol is encapsulated within lipoproteins, which are complex discoidal particles composed of amphiphilic proteins and lipids. Their outward-facing surfaces are water-soluble, while their inward-facing surfaces are lipid-soluble, enabling cholesterol to traverse the bloodstream via emulsification. Unbound cholesterol, being amphipathic, is transported within the monolayer surface of the lipoprotein particle, alongside phospholipids and proteins. Conversely, cholesterol esters, which are bound to fatty acids, are carried within the hydrophobic core of the lipoprotein, co-transported with triglycerides.
The blood contains several distinct types of lipoproteins, categorized by increasing density: chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). A lower protein-to-lipid ratio corresponds to a less dense lipoprotein. Although the cholesterol within these various lipoproteins is chemically identical, some are transported in their native "free" alcohol form, with the cholesterol-OH group oriented towards the aqueous environment surrounding the particles, while others are carried as fatty acyl esters, also known as cholesterol esters, within the particle's interior.
Lipoprotein particles are structurally organized by complex apolipoproteins, typically comprising 80 to 100 different proteins per particle. These apolipoproteins are recognized and bound by specific receptors on cell membranes, which direct the lipid payload into target cells and tissues that are actively internalizing these fat transport particles. These surface receptors function as unique molecular signatures, thereby influencing the distribution of fats throughout the body.
Chylomicrons, which represent the least dense cholesterol transport particles, incorporate apolipoprotein B-48, apolipoprotein C, and apolipoprotein E (the primary cholesterol carrier in the brain) within their outer shells. Chylomicrons are responsible for transporting fats from the intestine to muscles and other tissues requiring fatty acids for energy production or lipid synthesis. Any unutilized cholesterol persists within more cholesterol-rich chylomicron remnants, which are subsequently absorbed from the bloodstream by the liver.
VLDL particles are synthesized by the liver from triacylglycerol and cholesterol not utilized in bile acid synthesis. These particles contain apolipoprotein B100 and apolipoprotein E in their shells and can be catabolized by lipoprotein lipase on the arterial wall to form IDL. This enzymatic cleavage on the arterial wall facilitates the absorption of triacylglycerol and elevates the concentration of circulating cholesterol. IDL particles then undergo two distinct metabolic fates: approximately half are metabolized by hepatic triglyceride lipase (HTGL) and internalized by LDL receptors on liver cell surfaces, while the remaining half continue to lose triacylglycerols in the bloodstream until they transform into cholesterol-enriched LDL particles.
LDL particles serve as the primary transporters of cholesterol within the bloodstream. Each particle typically encapsulates approximately 1,500 molecules of cholesterol ester. The outer shell of an LDL particle features a single molecule of apolipoprotein B100, which is specifically recognized by LDL receptors located in peripheral tissues. Following the binding of apolipoprotein B100, numerous LDL receptors aggregate within clathrin-coated pits. Subsequently, both the LDL particle and its receptor are internalized into the cell through endocytosis, forming vesicles. These vesicles then merge with lysosomes, where lysosomal acid lipase catalyzes the hydrolysis of cholesterol esters. The liberated cholesterol can then be utilized for membrane biosynthesis or esterified for intracellular storage, thereby preventing disruption to cellular membranes.
LDL receptors are consumed during the process of cholesterol uptake, and their synthesis is precisely regulated by SREBP (sterol regulatory element-binding protein). SREBP is the same protein responsible for controlling the de novo synthesis of cholesterol, with its activity modulated by the intracellular cholesterol concentration. In cells with ample cholesterol, the synthesis of LDL receptors is inhibited, thereby preventing further uptake of cholesterol from circulating LDL particles. Conversely, when cellular cholesterol levels are insufficient, LDL receptor synthesis is upregulated to facilitate cholesterol acquisition.
Dysregulation of this process leads to the accumulation of LDL particles lacking receptor binding in the bloodstream. These circulating LDL particles undergo oxidation and are subsequently internalized by macrophages, which then transform into lipid-laden foam cells. Foam cells frequently become embedded within arterial walls, contributing significantly to the formation of atherosclerotic plaques. Variations in cholesterol homeostasis demonstrably influence the progression of early atherosclerosis, as evidenced by carotid intima-media thickness. These plaques represent primary etiological factors for myocardial infarctions, strokes, and other severe cardiovascular pathologies, which has led to the common designation of 'LDL cholesterol' (which is, in fact, a lipoprotein) as 'bad' cholesterol.
HDL particles are believed to facilitate the efflux of cholesterol from peripheral tissues back to the liver, either for biliary excretion or for utilization by hormone-synthesizing tissues. This crucial process is termed reverse cholesterol transport (RCT). Elevated concentrations of HDL particles are correlated with improved health outcomes, while diminished HDL levels are associated with the progression of atheromatous disease within the arteries.
Metabolism, Recycling, and Excretion
Cholesterol is prone to oxidation, readily forming oxygenated derivatives known as oxysterols. These compounds can arise through three distinct pathways: autoxidation, secondary oxidation resulting from lipid peroxidation, and enzymatic oxidation catalyzed by cholesterol-metabolizing enzymes. Significant scientific interest in oxysterols emerged upon the discovery of their inhibitory effects on cholesterol biosynthesis, a concept subsequently termed the 'oxysterol hypothesis'. Furthermore, oxysterols play diverse roles in human physiology, including their involvement in bile acid synthesis, serving as transport forms of cholesterol, and modulating gene transcription.
In biochemical investigations, radiolabeled cholesterol derivatives, such as tritiated-cholesterol, are frequently employed. However, these derivatives are susceptible to degradation during storage, necessitating the purification of cholesterol before experimental use. Cholesterol can be effectively purified using small Sephadex LH-20 columns.
The liver oxidizes cholesterol into various bile acids. These bile acids are subsequently conjugated with glycine, taurine, glucuronic acid, or sulfate. A composite of conjugated and unconjugated bile acids, alongside cholesterol itself, is then secreted from the liver into the bile. Approximately 95% of these bile acids are reabsorbed from the intestines, while the remaining fraction is eliminated in the feces. This cyclical process of bile acid excretion and reabsorption constitutes the enterohepatic circulation, which is vital for the digestion and absorption of dietary lipids. Under specific conditions, particularly when highly concentrated, such as within the gallbladder, cholesterol can crystallize and form the primary component of most gallstones; although lecithin and bilirubin gallstones also occur, they are less common. Daily, up to one gram of cholesterol enters the colon, originating from dietary intake, bile, and desquamated intestinal cells. This colonic cholesterol can be metabolized by resident bacteria, primarily converting it into coprostanol, a nonabsorbable sterol that is subsequently excreted in the feces.
Despite cholesterol's typical association with mammalian biology, the human pathogen Mycobacterium tuberculosis possesses the capacity for its complete degradation. This organism harbors numerous genes whose expression is modulated by cholesterol, many of which are homologous to fatty acid β-oxidation genes. These genes have undergone evolutionary adaptation to facilitate the binding of substantial steroid substrates, including cholesterol.
Dietary Sources
Animal fats comprise intricate blends of triglycerides, alongside smaller proportions of phospholipids and cholesterol, which are fundamental components of all animal (and human) cell membranes. Given that all animal cells synthesize cholesterol, every animal-derived food product inherently contains cholesterol in diverse concentrations. Prominent dietary contributors of cholesterol encompass red meat, egg yolks, whole eggs, liver, kidney, giblets, fish oil, shellfish, and butter. Furthermore, human breast milk also presents substantial cholesterol levels.
Plant cells produce cholesterol as a precursor for various other compounds, including phytosterols and steroidal glycoalkaloids; consequently, cholesterol is present in plant-based foods only in negligible quantities or is entirely absent. Certain plant foods, such as avocados, flax seeds, and peanuts, contain phytosterols. These compounds competitively inhibit cholesterol absorption within the intestines, thereby diminishing the uptake of both dietary and bile-derived cholesterol. A standard diet typically provides approximately 0.2 grams of phytosterols, an amount insufficient to significantly impede cholesterol absorption. However, phytosterol intake can be augmented via functional foods or dietary supplements enriched with phytosterols, which are acknowledged for their potential to lower LDL-cholesterol levels.
Medical Guidelines and Recommendations
In 2015, the scientific advisory panel, representing the U.S. Department of Health and Human Services and the U.S. Department of Agriculture for the 2015 edition of the Dietary Guidelines for Americans, rescinded the prior recommendation limiting dietary cholesterol consumption to 300 mg per day. This was replaced with a new directive to "eat as little dietary cholesterol as possible," thereby recognizing a correlation between a low-cholesterol diet and a diminished risk of cardiovascular disease.
A 2013 publication from the American Heart Association and the American College of Cardiology advocated for prioritizing healthy dietary patterns over adherence to specific cholesterol limits, citing the practical difficulties for both clinicians and consumers in implementing such restrictions. These organizations endorsed the DASH and Mediterranean diets, both characterized by their low cholesterol content. Subsequently, a 2017 review issued by the American Heart Association advised substituting saturated fats with polyunsaturated fats to mitigate cardiovascular disease risk.
Certain supplementary guidelines have proposed daily phytosterol dosages ranging from 1.6 to 3.0 grams (Health Canada, EFSA, ATP III, FDA). A meta-analysis revealed a 12% decrease in LDL-cholesterol levels with an average daily intake of 2.1 grams. However, the overall benefits of phytosterol-supplemented diets have also been subject to scrutiny.
Clinical Significance
Hypercholesterolemia
Consistent with the lipid hypothesis, elevated circulating cholesterol concentrations are implicated in the pathogenesis of atherosclerosis, potentially augmenting the risk of myocardial infarction, stroke, and peripheral artery disease. Given that elevated blood LDL—particularly higher LDL concentrations and smaller LDL particle size—contributes more significantly to this pathological process than the cholesterol content within HDL particles, LDL particles are frequently designated as "bad cholesterol." Conversely, high concentrations of functional HDL, capable of extracting cholesterol from cells and atheromas, confer protective effects and are commonly termed "good cholesterol." While these homeostatic balances are predominantly genetically predisposed, they are modifiable by factors such as body composition, pharmacological interventions, diet, and other environmental influences. A 2007 investigation revealed an exponential correlation between total blood cholesterol levels and both cardiovascular and overall mortality, with this association being more pronounced in younger individuals. Nevertheless, because cardiovascular disease is comparatively uncommon in younger demographics, the health impact of elevated cholesterol is more substantial in older populations.
Elevated levels of specific lipoprotein fractions—low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), and very-low-density lipoprotein (VLDL)—rather than total cholesterol, correlate with the extent and progression of atherosclerosis. Conversely, total cholesterol levels may remain within normal ranges while being predominantly composed of small LDL and small high-density lipoprotein (HDL) particles, a condition associated with high rates of atheroma growth. A post hoc analysis of the IDEAL and EPIC prospective studies identified an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and an elevated risk of cardiovascular disease, thereby questioning the previously assumed cardioprotective role of "good cholesterol".
Approximately one in 250 individuals possesses a genetic mutation affecting the LDL cholesterol receptor, which leads to familial hypercholesterolemia. Other forms of inherited hypercholesterolemia can involve genetic mutations within the PCSK9 gene and the gene encoding apolipoprotein B.
Elevated cholesterol levels are amenable to treatment through dietary modifications that reduce or eliminate saturated and trans fats, frequently supplemented by various hypolipidemic agents. These agents include statins, fibrates, cholesterol absorption inhibitors, monoclonal antibody therapies (specifically PCSK9 inhibitors), nicotinic acid derivatives, or bile acid sequestrants. Numerous international guidelines exist for the management of hypercholesterolemia.
Human trials utilizing HMG-CoA reductase inhibitors, commonly known as statins, have consistently confirmed that modifying lipoprotein transport patterns from unhealthy to healthier profiles significantly reduces cardiovascular disease event rates, even in individuals with cholesterol values currently considered low for adults. Studies have demonstrated that reducing LDL cholesterol levels by approximately 38.7 mg/dL with statin use can decrease cardiovascular disease and stroke risk by about 21%. Furthermore, research has indicated that statins mitigate atheroma progression. As a result, individuals with a history of cardiovascular disease may benefit from statins irrespective of their cholesterol levels (e.g., total cholesterol below 5.0 mmol/L [193 mg/dL]), and in men without cardiovascular disease, lowering abnormally high cholesterol levels provides a benefit, known as 'primary prevention'. Primary prevention in women was initially based on extrapolations from male studies, as no large statin trials conducted prior to 2007 in women demonstrated a significant reduction in overall mortality or cardiovascular endpoints. Nevertheless, meta-analyses have since shown significant reductions in all-cause and cardiovascular mortality, without significant heterogeneity by sex.
The 1987 report from the National Cholesterol Education Program's Adult Treatment Panels suggested specific total blood cholesterol levels: less than 200 mg/dL for normal, 200–239 mg/dL for borderline-high, and greater than 240 mg/dL for high cholesterol. The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and their associated risk for heart disease. Statins are effective in lowering LDL cholesterol and are widely utilized for primary prevention in individuals at high risk of cardiovascular disease, as well as for secondary prevention in those who have developed the condition. The global average mean total cholesterol for humans, both crude and age-standardized, has remained at approximately 4.6 mmol/L (178 mg/dL) for men and women for nearly 40 years, from 1980 to 2018, with observed regional variations and a reduction in total cholesterol in Western nations.
Contemporary diagnostic methodologies enable the separate determination of low-density lipoprotein (LDL), often termed 'bad' cholesterol, and high-density lipoprotein (HDL), referred to as 'good' cholesterol, thereby facilitating a more nuanced analysis of cholesterol profiles. A desirable LDL level is generally considered to be less than 100 mg/dL (2.6 mmol/L).
Total cholesterol is defined as the sum of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL). Typically, only total cholesterol, HDL, and triglycerides are directly measured. For reasons of cost-efficiency, VLDL is commonly estimated as one-fifth of the triglyceride concentration, and LDL is subsequently estimated using the Friedewald formula (or a variant thereof): estimated LDL = [total cholesterol] − [total HDL] − [estimated VLDL]. Direct LDL measurements are utilized when triglyceride levels exceed 400 mg/dL, as the estimation of VLDL and LDL becomes less accurate under such conditions.
The Framingham Heart Study revealed that a 10 mg/dL (0.6 mmol/L) increment in total cholesterol levels correlated with a 5% rise in 30-year overall mortality and a 9% increase in cardiovascular disease (CVD) mortality. Conversely, individuals over 50 years old experienced an 11% increase in overall mortality and a 14% increase in CVD mortality for every 1 mg/dL (0.06 mmol/L) annual reduction in total cholesterol. Researchers posited that this inverse correlation stemmed from underlying diseases increasing mortality risk and concurrently altering factors like weight loss and appetite suppression, which subsequently reduce serum cholesterol. The Vorarlberg Health Monitoring and Promotion Programme corroborated this effect in men of all ages and women over 50, observing higher mortality rates from cancer, liver diseases, and mental illnesses in these groups when total cholesterol levels were very low (186 mg/dL or 10.3 mmol/L and below). This finding suggests that the low-cholesterol effect is present even in younger populations, challenging earlier assumptions that it primarily serves as a marker for age-related frailty in older cohorts.
Hypocholesterolemia
The condition characterized by abnormally low cholesterol concentrations is designated as hypocholesterolemia. Investigations into the etiology of this state remain comparatively restricted; however, certain studies indicate potential associations with depression, various cancers, and cerebral hemorrhage. Generally, diminished cholesterol levels appear to be a sequela of an underlying pathology rather than its primary cause. Smith–Lemli–Opitz syndrome, a genetic disorder involving a defect in cholesterol synthesis, frequently presents with reduced plasma cholesterol. Furthermore, hyperthyroidism or other endocrine dysfunctions that induce upregulation of the LDL receptor can also precipitate hypocholesterolemia.
Testing
The American Heart Association advises cholesterol screening every four to six years for individuals aged 20 years and above. Distinct guidelines from the American Heart Association, published in 2013, specify that patients receiving statin therapy should undergo cholesterol assessment 4–12 weeks following their initial dose, with subsequent evaluations occurring every 3–12 months. For males between 45 and 65 years and females between 55 and 65 years, cholesterol testing is recommended biennially, while annual testing is advised for individuals over 65 years of age.
Following a 12-hour fasting period, a healthcare professional obtains a blood sample from a brachial vein to determine a comprehensive lipid profile, encompassing measurements for a) total cholesterol, b) HDL cholesterol, c) LDL cholesterol, and d) triglycerides. The reported results may be designated as "calculated," signifying that the values for total cholesterol, HDL, and triglycerides were derived through computation.
Cholesterol screening aims to ascertain "normal" or "desirable" levels, defined as a total cholesterol concentration of 5.2 mmol/L (200 mg/dL) or less, an HDL value exceeding 1 mmol/L (40 mg/dL, with higher values being more favorable), an LDL value below 2.6 mmol/L (100 mg/dL), and a triglyceride level under 1.7 mmol/L (150 mg/dL). However, for individuals presenting with lifestyle, age-related, or cardiovascular risk factors—including diabetes mellitus, hypertension, a family history of coronary artery disease, or angina—blood cholesterol parameters are assessed against modified thresholds.
Interactive pathway map
Cholesteric liquid crystals
Cholesteric liquid crystals
Certain cholesterol derivatives, alongside other straightforward cholesteric lipids, are recognized for their capacity to form the cholesteric liquid crystalline phase. This cholesteric phase, fundamentally a chiral nematic phase, exhibits thermochromic properties, altering its color in response to temperature fluctuations. Consequently, cholesterol derivatives find utility in temperature indication applications, such as liquid-crystal display thermometers and temperature-sensitive paints.
Stereoisomers
Cholesterol possesses 256 potential stereoisomers, originating from its eight stereocenters. Of these, only two stereoisomers hold biochemical relevance: nat-cholesterol and ent-cholesterol, representing the natural and enantiomer forms, respectively. The sole naturally occurring stereoisomer of cholesterol is nat-cholesterol.
Additional images
References
References
- Media related to Cholesterol at Wikimedia Commons