{
  "id": "cholesterol",
  "title": "Cholesterol",
  "lang": "en",
  "source_lang": "en",
  "summary": "Cholesterol is a sterol that stabilizes animal cell membranes and serves as the precursor of steroid hormones, bile acids and vitamin D; its blood levels are central to cardiovascular risk.",
  "category": "science",
  "subcategory": "biology",
  "type": "concept",
  "aliases": [
    "Cholesterin",
    "sterol (the broader class)"
  ],
  "generated_at": "2026-10-08",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/cholesterol/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/cholesterol/",
      "json": "https://aiwiki.page/zh/cholesterol.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "Cholesterol is a waxy, amphipathic sterol found in the membranes of animal cells. Its rigid four-ring steroid nucleus and single hydroxyl group let it insert between phospholipids and tune how fluid, thick and permeable a membrane is. Beyond its structural role, it is the starting material for steroid hormones, bile acids and vitamin D, and it is also involved in signalling by some membrane proteins. Because the body makes it in the endoplasmic reticulum and also takes it up from food, its levels are tightly regulated, and disturbances in that regulation are linked to cardiovascular disease and other conditions.\n\nThis entry covers cholesterol from its chemical structure and physical behaviour to its roles in membranes, its biosynthesis and cellular regulation, its transport in lipoproteins and its fate in the body. It then turns to the history of its discovery, its distribution across life, its connection with disease, the clinical measurement and guideline framework (including the 2026 ACC/AHA dyslipidemia guideline), and the drugs that act on its metabolism. The aim is to show how one molecule links basic biochemistry, membrane biology and medicine."
    },
    {
      "heading": "Chemical structure and nomenclature",
      "text": "Core skeleton and molecular formula\n\nCholesterol has the formula C27H46O and a molar mass of 386.65 g/mol. Its 27 carbons form a largely hydrocarbon framework, and the single oxygen is the only heteroatom, so the molecule is overwhelmingly nonpolar. The framework is the steroid nucleus, a fused, rigid system of four rings: three six-membered rings and one five-membered ring. Because the rings share edges, the core is stiff and nearly flat, with the two angular methyl groups (at C10 and C13) projecting from one face. That stiffness is one reason the molecule packs predictably among other lipids.\n\nFunctional features and their effects\n\nThree features shape the molecule's behaviour:\n\n- The 3β-hydroxyl group on ring A. It is the only polar functional group. Its β orientation places it on the same face as the angular methyls. It can hydrogen-bond with water and with phospholipid head groups, and it is the site where a fatty acid is attached to form a cholesteryl ester.\n- The C5–C6 double bond in ring B. It flattens part of the ring system and limits the conformational flexibility of ring B, which adds to the rigidity of the core.\n- The branched hydrocarbon side chain at C17 of ring D. It contains eight carbons and is nonpolar and flexible. It adds length and hydrophobic bulk, and it extends away from the ring system.\n\nName and classification\n\nThe IUPAC-style name is cholest-5-en-3β-ol. \"Cholest\" refers to the saturated 27-carbon parent, \"5-en\" marks the C5–C6 double bond, and \"3β-ol\" denotes a hydroxyl at C3 in the β orientation. The common name combines Greek \"chole\" meaning \"bile\" and \"stereos\" meaning \"solid,\" followed by the suffix \"-ol\" for \"alcohol.\" The name recalls its first identification in solid form, in gallstones: François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769, and in 1815, chemist Michel Eugène Chevreul named the compound \"cholesterine\".\n\nThe date at which the \"-ol\" ending was adopted is reported inconsistently. One account credits the German chemist Eugen Baumann with adding it in 1894, while another states that the name was changed in the early 20th century to follow IUPAC practice. Both agree that the final form signals an alcohol.\n\nChemically, cholesterol is a steroid that carries a hydroxyl group, so it is also an alcohol. It is therefore classed as a sterol, the subgroup of steroid alcohols.\n\nAmphipathic character and position in the cell\n\nCholesterol is only weakly amphipathic. Its polar head is a single small hydroxyl group, while the rest of the molecule is hydrocarbon. In water, the nonpolar body dominates: cholesterol is poorly soluble, with a reported value of 0.095 mg/L at 30 °C. In a lipid bilayer, the hydroxyl sits at the lipid–water interface, close to the phospholipid head groups, while the rigid ring system lies alongside the upper parts of the fatty acyl chains and the side chain extends toward the bilayer interior. This orientation lets the molecule share the membrane's hydrophobic core while keeping its one polar group in contact with the aqueous phase. Cholesterol's distribution among cellular membranes is covered in the membrane section."
    },
    {
      "heading": "Physical properties and stereochemistry",
      "text": "Cholesterol is a white, nearly odourless crystalline solid with the formula C27H46O and a molar mass of 386.65 g/mol. Its melting point is usually given as 148–150 °C for the anhydrous compound. Its water solubility is extremely low, although sources disagree on the exact figure: one compilation gives about 0.095 mg/L at 30 °C, while another gives about 1.8 mg/L at the same temperature. It dissolves readily in many organic solvents, including chloroform, hexane, ethanol, acetone and diethyl ether. Because almost the whole molecule is hydrocarbon and only the single 3β-hydroxyl group is polar, it cannot circulate freely in aqueous plasma. Instead it is carried inside lipoprotein particles, where phospholipids and apolipoproteins shield its hydrophobic body from water, and in the gut it is solubilised in bile micelles.\n\nIts tendency to crystallize is closely tied to its pathology. Cholesterol readily forms crystals, most often as thin plates, and the most clinically relevant form is the monohydrate, in which water molecules bridge neighbouring hydroxyl groups through hydrogen bonds in a triclinic lattice. The hydrate loses its water on moderate heating, at roughly 70–80 °C. Cholesterol monohydrate is the predominant crystalline form found in pathological deposits. Crystals of this type can make up to about 80% of the mass of gallstones, which form when bile becomes supersaturated with cholesterol. They also occur in atherosclerotic lesions, where cholesterol's poor water solubility favours its adhesion to hydrophobic surfaces in the arterial wall. Crystal habit and hydration state depend on the solvent: anhydrous crystals precipitate from anhydrous organic mixtures, whereas the monohydrate forms from aqueous mixtures, and plate-like morphology alone does not guarantee that the crystal is hydrated.\n\nCholesterol has eight stereocentres, located at C3, C8, C9, C10, C13, C14, C17 and C20. In the naturally occurring compound these carry the configuration commonly written as (3S,8S,9S,10R,13R,14S,17R) for the ring system, with the side-chain carbon C20 in the R configuration; the 3β-hydroxyl orientation is part of this description. This is why its IUPAC-style name is written as (3β)-cholest-5-en-3-ol. Its specific optical rotation is negative, about −40° in chloroform. The mirror image, ent-cholesterol, has the same formula and connectivity but is not recognised in the same way by many proteins and membranes. For this reason it is used in experiments as a stereochemical control to test whether a cholesterol effect depends on molecular shape. The stereochemistry also determines how the molecule packs with phospholipids and how its hydroxyl group is presented to binding partners.\n\nAnalytically, cholesterol must be distinguished from several close relatives. Cholestanol is the fully saturated analogue, lacking the C5–C6 double bond, and it has a different mass. Cholesterol biosynthetic precursors such as desmosterol and lathosterol differ only in the position or presence of double bonds, so they co-elute and require careful chromatography. Plant sterols such as sitosterol differ by an extra side-chain carbon (C29 rather than C27). Oxidised derivatives, or oxysterols, carry additional hydroxyl or keto groups. Oxidation of LDL cholesterol produces mainly 7β-hydroxycholesterol and 7-ketocholesterol, with smaller amounts of 4β- and 6β-hydroxycholesterol and the 5α,6α-epoxide. Gas chromatography–mass spectrometry is widely regarded as the reference method for oxysterol analysis, while liquid chromatography–mass spectrometry avoids the need for derivatization. Some pairs, such as the 24R/S-hydroxycholesterols and the 7α/7β-hydroxycholesterols, are hard to separate chromatographically, so selective ion monitoring or tandem mass spectrometry is used to distinguish them."
    },
    {
      "heading": "Sterols and cholesterol esters in biology",
      "text": "Cholesterol belongs to the sterol family, a class of lipids built on a fused four-ring steroid nucleus. Sterols, a class of lipids found in the cellular membranes of all eukaryotes, have vital roles in regulating membrane fluidity and permeability. Within this family, the major sterols differ mainly in their side chains. In animals, the major sterol is the much maligned cholesterol; in fungi, ergosterol; and in plants, β-sitosterol. It is evident from their structures that these three sterols are very similar, differing only by slight modifications to their floppy tails.\n\nPlant and fungal sterols\n\nPlants do not make cholesterol as their main sterol. While animal cells contain cholesterol in their membranes, plant cells contain phytosterols such as campesterol, sitosterol, and stigmasterol. These phytosterols form a group of structurally related compounds, and they are one reason cholesterol is often discussed alongside plant foods. Their biosynthesis diverges early: the three kingdoms have a common early synthetic pathway to squalene epoxide. After this compound, cycloartenol is produced in plants whereas squalene epoxide gives lanosterol in animals and fungi.\n\nFungi use ergosterol in the role that cholesterol plays in animal membranes. Ergosterol is a major product of sterol biosynthesis in fungi, playing a crucial role in membrane fluidity and the aerobic growth of most fungi. Chemically it is close to cholesterol: ergosterol contains two additional double bonds when compared to cholesterol and β-sitosterol. This structural difference is medically important, because the antifungal compounds' polyenes are more specific to ergosterol than cholesterol and thus have been widely used to treat fungal infections in animals. Azole drugs take the opposite approach and block the synthesis of ergosterol itself. Bacteria are a separate case: in bacterial membranes, sterol function is replaced by hopanoids, sterol-like lipids.\n\nFree cholesterol and cholesteryl esters\n\nCholesterol occurs in two chemical states. In the free form, the 3β-hydroxyl group is unmodified and the molecule can insert into membranes. In the esterified form, a fatty acid is joined to that hydroxyl group through an ester bond, producing a cholesteryl ester. The reaction is catalysed in the endoplasmic reticulum by acyl-CoA:cholesterol acyltransferase (ACAT), which takes free cholesterol and fatty acyl-CoA as substrates. The formation of cholesteryl ester from the esterification of free cholesterol and fatty acyl CoA is catalyzed by the microsomal acyl coenzyme A: cholesterol acyltransferase (ACAT).\n\nThe two forms have very different physical behaviour. Cholesterol is a lipid molecule; it partitions well within the phospholipid bilayer of various cell membranes. Unlike free (unesterified) cholesterol, the cholesteryl esters do not partition well within the lipid bilayer; instead, cholesteryl esters coalesce in aqueous medium and form cytoplasmic lipid droplets. Because esters do not take part in membrane structure, free cholesterol is largely confined to membranes, while esters accumulate in storage compartments.\n\nDistribution between free and esterified pools\n\nIn the circulation, esterified cholesterol is the larger fraction. Approximately one-third of cholesterol in plasma circulates as free cholesterol and approximately two-thirds as cholesteryl ester. Esters are preferred for transport because cholesterol esters, i.e., with long-chain fatty acids linked to the hydroxyl group, are much less polar than free cholesterol, and they are preferred for transport in plasma and as a biologically inert storage or de-toxification state to buffer an excess. Most of the body's cholesterol is distributed into cell membranes as the free form, so the ratio is not uniform across tissues. Tissues that handle large amounts of cholesterol for hormone production, or that take up lipoprotein cholesterol in excess, tend to hold a higher proportion as esters. In the adrenal glands and other steroidogenic tissues, ACAT-generated esters accumulate in cytosolic droplets where they can serve as cholesterol substrate stores for steroidogenesis. In macrophages, the same process produces esters that are stored as cytosolic lipid droplets, a characteristic feature of macrophage foam cells in atherosclerotic lesions.\n\nWhy esterification is regulated\n\nEsterification protects cells from an excess of free sterol. Free cholesterol that rises above what the membranes can hold is harmful, so cells convert the surplus into esters. The over accumulation of free cholesterol in the membranes can be cytotoxic to cells. Thus, a major function of ACATs is to protect against the unnecessary built up of free cholesterol within the cell membranes. The enzyme is itself responsive to the free cholesterol supply: intracellular free cholesterol also increases the activity of acyl CoA cholesterol acyltransferase (ACAT), the intracellular enzyme that converts free cholesterol to cholesteryl ester. Two ACAT isoforms have been described, and ACAT1/SOAT1 is ubiquitously expressed in nearly all tissues to maintain cholesterol homeostasis, whereas ACAT2 is mainly found in the liver and intestine. Esters are also needed for lipoprotein assembly in the intestine and liver, which is a further reason the process is tightly controlled."
    },
    {
      "heading": "Role in cell membranes",
      "text": "In animal cells, cholesterol is a major structural lipid of the plasma membrane, where it can account for roughly 30–40 mol% of membrane lipids. Its four fused rings form a rigid, nearly flat steroid nucleus. Within the bilayer, this nucleus lies between the fatty acyl chains of phospholipids, and the 3β-hydroxyl group sits at the aqueous interface, where it forms hydrogen bonds with phospholipid head groups. The hydrocarbon body packs against neighbouring chains mainly through van der Waals contacts. Because the molecule is short and rigid, it fits into the gaps left by bent or kinked chains, which is the basis for its effects on membrane physical properties.\n\nCholesterol increases lipid packing and rigidity, but it does not freeze the membrane. Mixed with phospholipids, it reduces the area per lipid molecule, a condensing effect that makes the bilayer more tightly packed than an ideal mixture would be. It also restricts the conformational freedom of the acyl chains, so they spend more time in extended, all-trans configurations. The result is a stiffer, less deformable membrane. Despite this ordering, lipids and membrane proteins still diffuse laterally within the plane of the bilayer. Cholesterol slows this lateral diffusion modestly rather than immobilizing it, which is why the membrane remains fluid in a functional sense.\n\nThe same ordering alters the bilayer's dimensions and barrier properties. Extended acyl chains make cholesterol-containing bilayers thicker than cholesterol-free ones, and this thickness difference can create hydrophobic mismatch with the transmembrane helices of some integral proteins, which may influence where those proteins prefer to reside. The tighter packing also reduces free volume within the bilayer core. As a result, cholesterol lowers the passive permeability of membranes to water, small polar molecules, protons and small ions, which helps the cell maintain its electrochemical gradients.\n\nCholesterol's most important physical role is its effect on phase behaviour. A pure phospholipid bilayer undergoes a phase transition from a tightly packed gel state at low temperature to a disordered liquid-crystalline state at higher temperature. Cholesterol broadens this transition, and at high concentrations it largely abolishes it, producing a liquid-ordered (Lo) phase in which chains are ordered yet lipids remain laterally mobile. Because the plasma membrane contains a high cholesterol fraction, it stays in this intermediate state across the range of temperatures a cell encounters. This buffers it against becoming too rigid in the cold and too fluid at body temperature, a balance that cells appear to actively maintain as part of membrane homeostasis. The domains that arise from this behaviour are discussed in the membrane domains section.\n\nCholesterol content is not uniform among cellular membranes. The plasma membrane holds most of the cell's unesterified cholesterol, often estimated at around 80–90%. By contrast, the endoplasmic reticulum, which is the main site of cholesterol synthesis, contains only a small fraction of the total, typically a few percent of the cell's cholesterol. The Golgi apparatus and endosomal and lysosomal compartments have intermediate levels, with late endosomes and lysosomes accumulating cholesterol abnormally in Niemann-Pick type C disease. Mitochondrial membranes, particularly the inner membrane, are also cholesterol-poor, and low cholesterol is thought to help preserve the fluidity needed for its protein-dense functions. The uneven distribution has a functional logic. The plasma membrane is the cell's principal cholesterol reservoir, because its high content of saturated phospholipids and sphingolipids, which pack well with cholesterol, favours retention of the molecule. Keeping the ER cholesterol-poor allows it to act as a sensitive sensor of sterol status for feedback regulation. Cholesterol is moved between compartments both by vesicular trafficking and by non-vesicular transfer at membrane contact sites, where lipid-transfer proteins shuttle the molecule against its concentration gradient."
    },
    {
      "heading": "Membrane domains and interactions with proteins",
      "text": "Liquid-ordered domains and lipid rafts\n\nCholesterol can drive lateral phase separation in the bilayer. Saturated acyl chains of sphingolipids allow close packing with one another, which probably leads to phase separation. Cholesterol then produces a liquid-ordered (Lo) region that is less fluid than the surrounding membrane. Compared with the bulk plasma membrane, which holds more unsaturated phospholipids, these rafts are enriched in cholesterol and sphingolipids. Biochemically, the most common working definition is the membrane fraction that resists extraction with nonionic detergents, although this is an indirect readout rather than a direct image of a domain.\n\nPhysically, rafts are small and transient structures, unlike the larger equilibrium domains seen in model membranes. Individually they appear small, but together they may make up a relatively large share of the plasma membrane. Whether they exist in living membranes at the sizes and lifetimes proposed remains debated.\n\nThe proposed functional role is spatial organization of signalling. Many signalling events seem to be concentrated in cholesterol-rich membrane domains rather than distributed randomly across the cell surface. A well-studied example is the Ras family: H-Ras is mostly found in cholesterol-enriched ordered domains, N-Ras sits largely at the boundary between ordered and disordered regions, and K-Ras associates with disordered domains. Thus, the lipid environment of a single protein family member can determine its signalling behaviour.\n\nDirect binding to ion channels and GPCRs\n\nCholesterol also acts on proteins directly, not only through the membrane. Structures of G protein-coupled receptors reveal several cholesterol sites, which may tune receptor dynamics and oligomerization. In the oxytocin receptor, cholesterol binds most stably when the receptor already carries an orthosteric ligand, and this stable interaction preserves cholesterol-dependent receptor activity even in cholesterol-depleted membranes. Using GPCR structures and binding assays, another study reported that membrane cholesterol can reach the orthosteric pocket of the adenosine A2A receptor from the membrane side and alter ligand binding. Some resolved cholesterols in GPCR crystal structures may be crystallization artefacts, so binding sites identified in static structures require functional confirmation.\n\nFor ion channels, the evidence is similarly structural. TRP channels are tetramers with large clefts between subunits, and cholesterol poses are located in hollows largely within these clefts. Cryo-EM structures of TRP channels have also captured bound cholesterol. Separating a direct effect from a membrane-mechanical one is difficult, because the observed effects of cholesterol on TRP function could follow from changes in membrane mechanics or from direct binding. In a pentameric ligand-gated channel, cholesterol occupies a site that also binds the drug ivermectin, which suggests a route for designing allosteric modulators. Overall, these lipid sites are regarded as allosteric and as potential drug targets. Multiple lipid binding sites on channels and receptors modulate function allosterically and may be druggable.\n\nCholesterol attachment to Hedgehog pathway proteins\n\nCholesterol is also covalently attached to signalling proteins. During maturation, the Hedgehog protein cleaves itself autocatalytically and acquires two lipid modifications, cholesterol and palmitate, a finding that established covalent lipid modification as a regulatory mechanism. The receptor-like transducer Smoothened (SMO) is also modified. SMO is covalently modified by cholesterol at the Asp95 residue through an ester bond. A D95N mutation that prevents this modification blocks Hedgehog-stimulated ciliary localization and downstream signalling. Developmental consequences follow. Homozygous knock-in mice carrying the equivalent mouse mutation are embryonic lethal with severe cardiac defects. Reduced activity of this pathway has been linked to developmental anomalies such as holoprosencephaly and brachydactyly.\n\nExperimental approaches\n\nDepletion experiments are a common way to test whether a process depends on cholesterol. Methyl-β-cyclodextrin (MβCD) extracts cholesterol from membranes, but its nonspecific effects must be controlled. In one T-cell study, 10–20% depletion increased tyrosine phosphorylation and activated ERK, and the raft marker GM1 aggregated upon depletion, with signalling proteins concentrating in these aggregated domains. To exclude nonspecific effects, the authors also used MβCD preloaded with cholesterol, which causes no net extraction, and the same results were obtained only with cholesterol depletion, supporting a cholesterol-specific effect.\n\nMolecular dynamics simulations complement these approaches by revealing binding poses that are hard to observe directly. Simulations and docking show that the hydroxyl groups of deeply buried cholesterol molecules can hydrogen-bond to acceptor and donor groups on membrane proteins. Simulations of a channel in a realistic neuronal membrane model have also shown that protein–lipid interactions depend on the channel's functional state. Functional assays in living cells, such as the ion channel-coupled receptor technique, can separate cholesterol effects from intracellular signalling, which helps interpret binding data."
    },
    {
      "heading": "Biosynthesis",
      "text": "From acetyl-CoA to squalene\n\nCholesterol is built from acetyl-CoA, a two-carbon unit that also feeds fatty acid synthesis. The pathway involves more than twenty enzymes and nearly thirty reactions, and it is commonly described in three stages. The first stage, often called the mevalonate arm, begins with acetyl-CoA consumed in parallel in the mitochondria, cytoplasm and peroxisomes, and ends with squalene forming in the endoplasmic reticulum. Acetyl-CoA is condensed into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which is reduced to mevalonate. Mevalonate is then converted into the five-carbon isoprene units isopentenyl pyrophosphate and dimethylallyl pyrophosphate, which combine into the 15-carbon farnesyl pyrophosphate (FPP). Two FPP molecules are joined tail to tail by squalene synthase (FDFT1) to give the 30-carbon linear triterpene squalene. Because FPP and other isoprenoid intermediates can be diverted to non-sterol products such as dolichols and ubiquinone, the squalene step is usually treated as the first step specific to sterol synthesis.\n\nCyclization and the two routes to cholesterol\n\nThe second stage starts with squalene epoxidase (SQLE), a monooxygenase that uses NADPH and molecular oxygen to place an epoxide across the 2,3 position of squalene. Lanosterol synthase then cyclizes the 2,3-oxidosqualene in a cascade that closes the rings of the steroid nucleus and produces lanosterol, the first true sterol. Lanosterol is not yet cholesterol. It still carries methyl groups at C4 and C14 and retains a side chain that must be modified. Lanosterol 14α-demethylase (CYP51A1) and a set of demethylases, reductases and isomerases remove the extra methyl groups, and a 3-keto intermediate is formed during C4 demethylation. The final conversion can proceed through two intersecting sequences, distinguished by when the C24 double bond in the side chain is reduced by 3β-hydroxysterol Δ24-reductase (DHCR24).\n\n- In the Bloch pathway, the C24 double bond is kept until the end, so the sterol desmosterol accumulates and DHCR24 reduces it in the final step.\n- In the Kandutsch–Russell pathway, DHCR24 acts early on lanosterol-derived intermediates, and the route passes through 7-dehydrocholesterol, which is reduced to cholesterol.\n\nThe two routes use largely the same enzymes and differ mainly in the presence or absence of that C24 double bond. Their relative use varies between tissues: tissues that synthesize large amounts of cholesterol rely mostly on the Bloch route, whereas tissues with low sterol synthesis mostly use a modified Kandutsch–Russell route. The shunt pathway that leads to 24(S),25-epoxycholesterol branches off after squalene and is a separate sterol arm.\n\nEnzymes, compartments and the rate-limiting step\n\nMost enzymes of the later stages are integral membrane proteins of the endoplasmic reticulum, particularly its smooth portion, so the synthetic machinery is physically anchored to the membrane system where its products are used. The upstream enzymes are partly cytoplasmic, which is why the pathway spans several compartments. The committed control point is HMG-CoA reductase (HMGCR), an ER membrane enzyme that converts HMG-CoA to mevalonate. Its activity is regulated by sterol feedback and by changes in its own abundance, and it is the target of statins (discussed in the pharmacology section). Squalene epoxidase is also described as a rate-limiting enzyme in the pathway, which means control is shared across more than one step rather than resting on HMGCR alone.\n\nShare of de novo synthesis versus dietary supply\n\nEstimates of the body's cholesterol budget vary, but the general picture is consistent. One review puts the daily requirement at about 1 g, of which roughly 600–900 mg comes from endogenous synthesis and about 300–500 mg is absorbed from food, a ratio of approximately 7:3. Another source gives a similar 70% de novo share for peripheral tissues, with the remaining 30% from diet. The contributions shift with diet. In a person who eats no cholesterol at all, the entire requirement of roughly 1–1.5 g per day must be met by synthesis. Synthesis is also tightly coupled to absorption and elimination: the liver and intestine adjust their output according to how much cholesterol arrives from food.\n\nWhere synthesis happens is also uneven. Estimates of organ shares differ by source and by metric. One review attributes about 50% of biosynthesis to the liver and about 24% to the intestine, whereas another source notes that the liver and intestine each account for about 10% of total body cholesterol. In the brain, the blood–brain barrier largely prevents uptake of lipoprotein-borne cholesterol, so the brain depends almost entirely on local synthesis, and its cholesterol turns over far more slowly than that of the periphery."
    },
    {
      "heading": "Regulation of cellular cholesterol homeostasis",
      "text": "Cells keep their free cholesterol within a narrow range by coupling a sensor in the endoplasmic reticulum (ER) to a set of transcription factors. The central sensor is SCAP (SREBP cleavage-activating protein). When sterol is abundant in the ER membrane, cholesterol binds to SCAP's sterol-sensing domain and shifts its shape so that it can grip Insig, an ER retention protein. The SCAP–SREBP complex then stays in the ER and the SREBP is not processed. When membrane sterol falls, SCAP releases Insig and packages the SCAP–SREBP complex into COPII vesicles bound for the Golgi apparatus. There, two sequential proteases (site-1 and site-2) cut SREBP, and the released N-terminal fragment travels to the nucleus. The SREBP-2 isoform in particular switches on most of the genes for cholesterol synthesis and uptake, so the system works as an on-off switch tied to the sterol content of the ER membrane.\n\nSynthesis is also controlled after transcription. HMG-CoA reductase, which catalyses the committed step of the mevalonate pathway, carries its own sterol-sensing region. Certain sterols and sterol intermediates promote its binding to Insig, which leads to ubiquitination and degradation by the proteasome. This sterol-accelerated degradation occurs alongside a transcriptional brake on the reductase gene and a reduction in translation of its mRNA. Oxysterols such as 25-hydroxycholesterol act mainly through Insig and block SREBP activation, whereas the intermediate 24,25-dihydrolanosterol accelerates reductase degradation without blocking SREBP-2 processing. The result is a double brake: the enzyme is made less and destroyed faster when sterol accumulates. When sterol is depleted, the reverse occurs, with more reductase mRNA and a longer-lived protein, which increases the flow of mevalonate.\n\nWhen cellular sterol is low, SREBP-2 also raises expression of the LDL receptor. Its gene is driven by SREBP together with cofactor proteins, so a cell that lacks cholesterol increases its capacity to capture cholesterol-rich LDL particles from the circulation. This is the reason that LDL receptor activity is closely linked to plasma cholesterol clearance in the liver, and the same feedback logic explains why statin treatment, which lowers intracellular sterol, induces receptor expression.\n\nExcess free cholesterol is not left in the membrane. The ER enzyme ACAT (acyl-CoA:cholesterol acyltransferase; ACAT1 in most macrophages and many other cells) esterifies the 3β-hydroxyl with a fatty acid, producing cholesteryl esters that are stored in cytoplasmic lipid droplets. Neutral cholesteryl ester hydrolases reverse this step, releasing free cholesterol when it is needed. Together the two activities act as a buffer that keeps the free pool in the membrane at an appropriate level. In macrophages, however, uptake of oxidized LDL can overload this buffer, and the accumulation of cholesteryl ester droplets produces the foam cells that characterise early atherosclerotic lesions. Because ester hydrolysis is generally considered the first and rate-limiting step for releasing cholesterol from cells, impaired hydrolysis reduces efflux even when acceptors are present.\n\nCells export surplus sterol mainly through ATP-binding cassette transporters. ABCA1 moves free cholesterol and phospholipids from the plasma membrane onto lipid-poor apolipoprotein A-I, generating nascent HDL particles. ABCG1 works on a different acceptor. Experimental models differ on its exact mechanism: one view holds that it transfers cholesterol to mature HDL particles, while another proposes that it enriches the plasma membrane with sterol from an intracellular pool and makes that sterol available to HDL. Simple diffusion and the scavenger receptor SR-BI also contribute. In most normal macrophages, simple diffusion, governed by the cholesterol concentration gradient, appears to dominate, whereas ABCA1 and ABCG1 become decisive in cholesterol-overloaded cells. Because peripheral cells cannot degrade cholesterol, efflux is effectively their only route for removing an excess, which is why defects in these transporters are associated with increased atherosclerosis risk."
    },
    {
      "heading": "Transport in blood and lipoproteins",
      "text": "Because cholesterol is hydrophobic, it cannot dissolve in plasma and travel freely. The body instead moves it inside lipoprotein particles, which are spherical assemblies of lipids and apolipoproteins with a hydrophobic core and a surface that faces the aqueous blood. Cholesterol is transported in the body via lipoproteins. The particles are commonly sorted by density and size into chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and the first four are classed as apoB-containing particles.\n\nParticle classes and their origins\n\nChylomicrons are built in the intestine. They are large and rich in triacylglycerol, and they carry dietary cholesterol to peripheral tissues and the liver. Each particle carries one apoB-48 molecule, a truncated form of apoB-100 produced only in enterocytes, because an RNA-editing step introduces an early stop codon. As the triglyceride core is hydrolysed by lipoprotein lipase, the particle shrinks into a remnant that the liver removes from the circulation.\n\nVLDL is assembled in the liver. Its protein composition resembles that of chylomicrons, but it contains apoB-100 and has a higher cholesterol-to-triglyceride ratio, which is roughly 1 mg of cholesterol per 5 mg of triglyceride. As VLDL loses triglyceride to lipoprotein lipase, it becomes IDL. When the cholesterol content of an IDL exceeds its triglyceride content, it is converted into LDL. LDL is the main cholesterol-carrying class in fasting plasma: LDL comprises the largest fraction of circulating lipoproteins, constituting about 60% to 70% of total cholesterol. Each LDL particle carries a single apoB-100 molecule, which wraps around the particle like a belt and stays attached throughout its journey from VLDL to LDL.\n\nHDL is different in structure. It is a protein-rich disc-shaped particle, about 8–10 nm in size, with lower cholesterol content, and its main apolipoprotein is apoA-I. Nascent HDL acquires phospholipids and cholesterol from cells and matures in the plasma.\n\nLDL uptake in peripheral tissues\n\nLDL delivers cholesterol to cells through the LDL receptor. The receptor binds apoB-100 on the particle, and receptors cluster in clathrin-coated pits so that the bound particle is internalised by endocytosis. After internalisation, the complex reaches endosomes, where acidification weakens the binding, releasing the particle's cargo, while the receptor is recycled back to the surface. The LDL particle is then broken down in lysosomes, which releases free cholesterol into the cell. Because LDL receptor expression is itself controlled by the cell's sterol content, the amount of uptake is adjusted according to need; the feedback system is described in the regulation section. Loss of LDL receptor function causes familial hypercholesterolaemia, in which plasma LDL cholesterol rises and atherosclerosis develops early.\n\nHDL and reverse cholesterol transport\n\nHDL is central to reverse cholesterol transport (RCT), the process that removes excess cholesterol from peripheral cells and returns it to the liver. The liver secretes lipid-poor apoA-I, which picks up cholesterol through the ABCA1 transporter. Mature HDL is then formed with the help of lecithin-cholesterol acyltransferase (LCAT), which esterifies the cholesterol so that it is retained inside the particle. Cholesterol is also effluxed from macrophages through ABCG1 to mature HDL. Mature HDL can deliver its cholesteryl esters to the liver in two ways. The scavenger receptor SR-BI selectively takes up the esters without internalising the whole particle, or cholesteryl ester transfer protein (CETP) moves the esters onto apoB-containing particles, which the liver then clears through LDL receptors. In the liver, cholesterol may be excreted directly into bile or converted into bile acids. Fundamentally, RCT is a transport route whose efficiency depends on the function of the transporters and receptors rather than on the amount of HDL cholesterol alone.\n\nWhy \"good\" and \"bad\" cholesterol are simplifications\n\nThe labels \"good\" cholesterol (HDL) and \"bad\" cholesterol (LDL) describe the cargo rather than the biology of the particles. LDL and HDL carry the same molecule, so the terms say little about why each particle behaves as it does. Particle number and apolipoprotein content matter as much as cholesterol mass: LDL particles constitute 90% of circulating apoB-containing lipoproteins, with each LDL particle containing a single apoB-100 molecule. Two particles with the same LDL cholesterol content can therefore differ in how many apoB particles are present. For HDL, the picture is also not monotonic. One review states that too much HDL cholesterol can be as harmful as too little, and that there is no evidence that HDL-increasing drugs acting through enhanced ABCA1 expression prevent atherosclerotic cardiovascular disease in humans. These points are why clinical assessment increasingly considers apoB and non-HDL cholesterol alongside the conventional labels."
    },
    {
      "heading": "Dietary intake and absorption",
      "text": "Dietary sources and the intestinal uptake route\n\nDietary cholesterol comes mainly from animal-derived foods such as egg yolk, meat, shellfish, butter and other dairy products. Plant foods supply little cholesterol and instead provide phytosterols, which are structurally similar but chemically distinct. Absorption takes place in the small intestine. Free cholesterol is taken up by the enterocytes through NPC1L1, a multi-spanning transmembrane protein on the brush-border membrane. NPC1L1 internalizes cholesterol by vesicular endocytosis. Estimates from human studies suggest that more than half of the cholesterol passing through the intestine is absorbed. Because biliary cholesterol secreted into the duodenum is also taken up by NPC1L1, the pool available for absorption is larger than the amount eaten.\n\nUptake depends on cholesterol being carried into the gut lumen in mixed micelles, which form with bile salts. The efficiency of cholesterol delivery to NPC1L1 therefore depends partly on bile salt concentration. After endocytosis, bile acids appear to help move cholesterol from the endocytic recycling compartment to the endoplasmic reticulum, which allows NPC1L1 to return to the plasma membrane for another round of uptake. Inside the enterocyte, cholesterol that reaches the endoplasmic reticulum is esterified by ACAT2 and incorporated into chylomicrons, the particles that carry dietary lipid into the lymph and then the blood. Genetic or pharmacological loss of NPC1L1 reduces cholesterol absorption by roughly 70% in mice, which shows that the transporter is the main, though not the only, route for dietary sterols. Ezetimibe, the only clinically approved NPC1L1 inhibitor, lowers circulating LDL cholesterol by about 20%.\n\nSelectivity against plant sterols\n\nNPC1L1 also transports plant sterols, vitamin E and vitamin K. Its N-terminal domain, however, binds cholesterol but not the plant sterols β-sitosterol and stigmasterol. This structural discrimination is thought to explain why cholesterol is absorbed preferentially, even though plant sterols use the same entry route. Because they share the transporter, plant sterols compete with cholesterol for uptake, and they are absorbed far less efficiently than cholesterol. Oxysterols add another layer of control: 25- and 27-hydroxycholesterol compete with cholesterol for the same binding site and inhibit NPC1L1-mediated endocytosis.\n\nFactors that influence absorption efficiency\n\nSeveral factors change how much of a meal's cholesterol enters the body. Protein structure matters: NPC1L1 functions largely as a homodimer, and monomeric forms show reduced cholesterol uptake in experimental systems. Common genetic variation also matters. Nonsynonymous NPC1L1 variants have been associated with lower absorption and lower LDL cholesterol, and loss-of-function variants with reduced coronary heart disease risk in a multi-ancestry cohort. Within one person, however, the fraction of a test dose of cholesterol that is absorbed tends to be highly reproducible when conditions are standardized. Pharmacological inhibition, bile acid handling and hepatic reabsorption of biliary cholesterol further shape the net flux.\n\nDietary cholesterol and blood cholesterol\n\nThe relationship between dietary cholesterol and blood cholesterol has been debated for decades. Early metabolic-ward studies from the 1950s and 1960s reported large responses, whereas later controlled studies in healthy adults on low-saturated-fat backgrounds found smaller ones. In one such study, each 100 mg per day of added dietary cholesterol raised LDL cholesterol by about 0.054 mmol/L, and about three-quarters of the rise in total cholesterol was attributable to LDL. The individual slopes, however, ranged from slightly negative to clearly positive. Other reviewers have concluded that dietary cholesterol content has only a small effect on plasma cholesterol, and this divergence is one reason why dietary guidelines have moved away from absolute cholesterol limits and toward emphasizing saturated fat.\n\nResponses also vary widely between people. In a feeding study on National Cholesterol Education Program Step 2 diets, changes in LDL cholesterol ranged from an increase of 3% to a decrease of 55% in men, and apolipoprotein E genotype was associated with the size of the response. In a family-based study comparing margarine with butter, family membership accounted for a substantial share of the variation, and body mass index also predicted how much LDL cholesterol fell.\n\nInteractions with saturated and trans fats\n\nSaturated fatty acids raise LDL cholesterol more consistently than most other dietary components. Replacing saturated fat with polyunsaturated fat lowers both total and LDL cholesterol in randomized trials, and replacing it with carbohydrate lowers these values but tends to raise triglycerides and lower HDL cholesterol. Monounsaturated fat has been studied less, and the results are largely null. Trans fats raise LDL cholesterol and lower HDL cholesterol, and they increase the ratio of total to HDL cholesterol, which is a more consistent signal than the effect of saturated fat on that ratio. Saturated fat also raises HDL cholesterol, which complicates its net effect on cardiovascular risk.\n\nThe response to saturated fat is strongly individual. In one study, a 6.1% increase in energy from saturated fat produced LDL changes ranging from roughly +45% to −20%. Food matrix matters as well: in a controlled comparison, a saturated-fat-matched cheese diet lowered LDL cholesterol slightly more than a butter diet. A Cochrane meta-analysis of randomized trials reported a 21% reduction in combined cardiovascular events when saturated fat was reduced for at least two years, and the authors linked part of this benefit to LDL reduction. Whether dietary cholesterol itself contributes independently to cardiovascular risk remains less settled than the evidence for saturated and trans fats."
    },
    {
      "heading": "Metabolic fates and excretion",
      "text": "Cholesterol that is not incorporated into membranes, lipoproteins or storage esters is metabolised in several directions. The largest route in terms of mass is conversion to bile acids in the liver. A smaller but functionally crucial share is converted into steroid hormones in endocrine tissues, and a tiny fraction is transformed in the skin into vitamin D3. The remainder leaves the body through bile and faeces, where gut bacteria can further modify it.\n\nBile acids and enterohepatic recycling\n\nBile acid synthesis is the main catabolic sink for cholesterol. The liver is the principal site, and cholesterol is the obligatory precursor. The classic (neutral) pathway begins with cholesterol 7α-hydroxylase (CYP7A1), a microsomal cytochrome P450 in the endoplasmic reticulum of hepatocytes, which adds a hydroxyl group at C7 to give 7α-hydroxycholesterol. This is the first and rate-limiting step, and the enzyme is expressed largely in the liver. The product is then converted to 7α-hydroxy-4-cholesten-3-one, from which the two primary bile acids in humans, cholic acid and chenodeoxycholic acid, are generated, with the sterol nucleus and side chain both modified. A second, \"alternative\" (acidic) pathway begins with the mitochondrial enzyme CYP27A1, which oxidises the side chain first; it accounts for a minority of bile acid output in most people, while oxysterols made in extrahepatic tissues can also be converted to bile acids in the liver. Estimates of how much of cholesterol elimination runs through bile acid synthesis vary, but it is generally described as the larger of the two excretory routes.\n\nBile acids are conjugated with glycine or taurine, stored in the gallbladder, and released into the duodenum after meals, where they emulsify dietary fats and promote the absorption of fat-soluble vitamins. Their amphipathic structure allows them to form micelles with lipids. Most of the bile acid pool is reabsorbed in the distal ileum, roughly 90–95 per cent, and returned to the liver through the portal circulation; this closed loop is termed the enterohepatic circulation. Bacteria in the colon deconjugate and dehydroxylate the bile acids that escape reabsorption, producing secondary bile acids such as deoxycholic acid and lithocholic acid. Because the recycling is efficient, only a few hundred milligrams per day must be replaced by new synthesis, and the liver adjusts CYP7A1 activity in response to the returning bile acids through the nuclear receptor FXR and the hormone FGF19 signalling axis.\n\nSteroid hormones\n\nAll steroid hormones of vertebrates are built from cholesterol, and the first committed step is shared by every steroidogenic tissue. In the inner mitochondrial membrane, the cytochrome P450 side-chain cleavage enzyme (P450scc, encoded by CYP11A1) performs three successive monooxygenase reactions on the side chain, first hydroxylating C22 and then C20, and finally cleaving the C20–C22 bond. The products are pregnenolone, a C21 steroid, and isocaproaldehyde. Each catalytic cycle consumes NADPH and oxygen, and electrons are delivered by the ferredoxin-type proteins adrenodoxin and adrenodoxin reductase. This reaction is generally regarded as the rate-limiting step of steroidogenesis, which is why the supply of cholesterol to the mitochondria is itself tightly controlled.\n\nFrom pregnenolone, the pathway branches. Conversion to progesterone and then to the corticosteroids, including aldosterone (a mineralocorticoid) and cortisol (a glucocorticoid), occurs mainly in the adrenal cortex, while the Δ5 and Δ4 routes produce androgens such as dehydroepiandrosterone and testosterone, with the gonads and adrenals as the main sources. Removing the C19 methyl group from androgens leads to the C18 estrogens, and aromatase converts androgens to estrogens in target tissues. Progestogens, mineralocorticoids, glucocorticoids, androgens and estrogens therefore all share the same early sequence, and the tissue-specific complement of enzymes determines which product dominates. Cortisol and aldosterone are produced in the adrenal glands; sex steroids in the gonads and placenta.\n\nVitamin D3 synthesis in skin\n\nCholesterol is also the source of vitamin D3, but through a photochemical rather than enzymatic route. The immediate precursor is 7-dehydrocholesterol (7-DHC), a sterol with a conjugated diene in ring B that is found mainly in the epidermis and, to a lesser extent, the dermis. It absorbs ultraviolet B light most effectively between roughly 290 and 320 nm. Absorption opens ring B and produces previtamin D3, which then undergoes a temperature-dependent, non-enzymatic isomerisation, which is rapid at skin temperature, to form vitamin D3 (cholecalciferol). The newly formed vitamin D3 enters the dermal capillaries and is carried to the liver, where it is hydroxylated to 25-hydroxyvitamin D3, and subsequently in the kidney to the active hormone 1,25-dihydroxyvitamin D3. Prolonged UVB exposure also drives previtamin D3 towards inactive photoproducts such as lumisterol and tachysterol, which limits the amount of vitamin D3 the skin can make. Melanin competes with 7-DHC for UVB photons, so pigmentation reduces output at a given exposure. Because the process depends on sunlight, dietary intake and other sources also contribute to vitamin D status.\n\nExcretion through bile and faeces\n\nCholesterol itself leaves the body in two main ways: as free cholesterol secreted into bile by the ATP-binding cassette transporters ABCG5 and ABCG8, and as bile acids. Biliary cholesterol enters the intestinal lumen, where a portion is absorbed again, while the remainder reaches the faeces. Faecal neutral sterols contain substantial amounts of cholesterol that the body did not reabsorb, together with its reduced metabolites. In the colon, many intestinal bacteria reduce the Δ5 double bond of cholesterol, converting it to coprostanol (5β-cholestan-3β-ol), which is poorly absorbed. This microbial transformation is considered a significant route for cholesterol removal in some species, and differences in gut microbiota are thought to contribute to inter-individual variability in faecal sterol excretion. Because coprostanol is not readily reabsorbed, its formation effectively removes cholesterol from the body."
    },
    {
      "heading": "Evolution and distribution across life",
      "text": "The identity of the dominant sterol differs among eukaryotic kingdoms. Animals primarily produce cholesterol, fungi mainly synthesize ergosterol, and plants produce phytosterols such as sitosterol, stigmasterol, and campesterol. Structurally, cholesterol is a C27 sterol, while the principal fungal and plant sterols carry 28 or 29 carbons. Cholesterol differs from C28 and C29 sterols by only one methyl or ethyl group at position C24. The enzyme that adds this group, C-24 sterol methyltransferase, is widely distributed in plants, microbial eukaryotes, and fungi but is not known from nearly all animals, with some marine sponges and the marine annelid Capitella teleta as the exceptions. The animal-versus-plant division is also not absolute: in certain gutless marine worms, the plant-type sterol sitosterol is the most abundant sterol present.\n\nFungi show a more complicated pattern than the textbook \"ergosterol kingdom\" suggests. Surveys of 175 species indicate a clear trend from cholesterol and other Δ5 sterols in the earliest diverging fungal species to ergosterol in later diverging fungi. Other departures from ergosterol as the dominant sterol include 24-ethyl cholesterol in Glomeromycota, brassicasterol in Taphrinales, and cholesterol in Pneumocystis. One proposal links the spread of ergosterol to life on land: its protective effect against mechanical and oxidative stress may have been favoured by repeated wetting and drying in terrestrial habitats. This explanation is still debated, and the reason for the evolutionary choice of most fungi being ergosterol is still debated.\n\nOxygen is central to the sterol pathway, and this separates sterol synthesis from older membrane lipids. Cholesterol synthesis is highly oxygen-consuming, with 11 molecules of oxygen required to generate one molecule of cholesterol. The first enzymatic step in sterol production requires molecular oxygen. By contrast, many prokaryotes produce hopanoids, sterol-like compounds that are synthesized from the common precursor squalene without the use of molecular oxygen. Oxygen-independent chemistry also appears on the degradative side: Sterolibacterium denitrificans can degrade cholesterol regardless of the presence of oxygen. The cyclase that forms the steroid skeleton is thought to be ancient; oxidosqualene cyclase, responsible for sterol cyclization, is thought to have evolved around the Great Oxidation Event. Some authors have suggested that sterols first arose as a way to limit oxygen diffusion across membranes, and that the rise in atmospheric oxygen then favoured their production. This is a hypothesis rather than an established conclusion.\n\nSterol synthesis in bacteria is patchy and has long been regarded as secondary to the eukaryotic pathway. Several bacteria, including aerobic methanotrophs, Planctomycetes, and various myxobacteria, are known to produce sterols de novo. Unlike eukaryotes, these bacteria largely produce lanosterol, parkeol, or cycloartenol, the initial cyclization products of oxidosqualene cyclase. Until recently, no bacterium had been shown to synthesize highly modified eukaryotic sterols, such as cholesterol. A later study showed that two phylogenetically distinct bacteria, Enhygromyxa salina and Calothrix sp. NIES-4105, are capable of de novo cholesterol production. Their C-4 demethylation step is carried out by bacterial proteins that differ from the eukaryotic ones. Whether this capacity was acquired by horizontal gene transfer from eukaryotes or reflects an older bacterial origin remains unresolved. The horizontal-transfer idea is supported by the rarity and uneven distribution of sterol biosynthesis across bacterial phyla, while recent phylogenetic and structural analyses of OSC and the C-14 demethylase (CYP51) suggest a bacterial origin for these proteins.\n\nWithin eukaryotes, the sterol pathway is built on a conserved core. Eukaryote lineages exhibit a conserved framework for sterol biosynthesis inherited from their last common ancestor. The route runs from mevalonate to squalene, and oxidosqualene cyclization is carried out by lanosterol synthase in animals and cycloartenol synthase in plants. In plants, cholesterol is a minor sterol and is produced from cycloartenol following a pathway similar to that of phytosterol synthesis. Because the same enzymes can act on precursors from either branch, the two routes diverge only after cycloartenol is formed. Phylogenetic work suggests that most enzymes for the biosynthesis of plant, fungal, and animal sterols were present in the last eukaryotic common ancestor, with the distribution observed in most extant eukaryotes evolving through multiple events of enzyme losses and different pathways for sterol synthesis. Conserved enzymes therefore serve as markers of lineage history: the presence of CPI1 in four green algal genomes was read as evidence for the cycloartenol branch seen in higher plants, and phylogenomic analysis argues that if the ancestral eukaryote had CPI1, it used a cycloartenol route rather than a lanosterol route. These inferences depend on the completeness of genome data and on how confidently enzyme homologues are assigned."
    },
    {
      "heading": "Cholesterol and disease",
      "text": "The disease most directly tied to cholesterol is atherosclerosis, the arterial lesion that underlies most cardiovascular disease. Clinical and mechanistic work treats low-density lipoprotein cholesterol (LDL-C) as a causal and cumulative factor in this process. Early lesions begin when LDL particles enter the intima and stay there. They accumulate in plaques, presumably because they interact with intimal proteoglycans. Trapped particles are then altered chemically. Metal ions and enzymes such as myeloperoxidase and 12/15-lipoxygenase can catalyse LDL oxidation. Macrophages take up the modified particles through scavenger receptors, whereas unmodified LDL enters macrophages too slowly to explain foam cell formation, because LDL receptors are downregulated in these cells. The resulting lipid-laden foam cells are the characteristic cell of the early lesion. Oxidized particles also impair endothelial function and promote monocyte chemotaxis and smooth muscle cell migration, eventually destabilizing plaques and leading to rupture.\n\nLowering LDL-C is the main therapeutic lever. Intensive LDL-C lowering with statins, ezetimibe, PCSK9 inhibitors and newer agents has shown benefit in regressing plaques, stabilizing their morphology and reducing cardiovascular events. The 2026 United States guideline sets treatment goals by risk category. It is a comprehensive replacement of the 2018 US guideline on blood cholesterol. For adults with borderline or intermediate 10-year risk, it is reasonable to treat to an LDL-C goal below 100 mg/dL and non-HDL-C below 130 mg/dL when starting statin therapy. For established disease, an LDL-C goal below 70 mg/dL remains appropriate for patients with established ASCVD who do not meet very-high-risk criteria. Patients at very high risk of ASCVD events are given a goal of LDL-C below 55 mg/dL and non-HDL-C below 85 mg/dL. The guideline also recommends that lipoprotein(a) be measured at least once during adulthood.\n\nInherited disorders show the causal role of LDL clearance most clearly. Familial hypercholesterolemia (FH) is an autosomal disorder in which the LDL receptor is defective in more than 75% of cases, owing to mutations in the LDLR gene. Less often, the cause lies in a gene for another molecule that interacts with the LDL receptor, such as apolipoprotein B or PCSK9, or in an unknown gene. The heterozygous form is the most common, with a prevalence of roughly 1 in 200 to 250 people, whereas the homozygous form occurs at about 1 in 250,000 to 360,000. Estimates vary across studies, and some patients with clinical FH (10%-40%) lack an identified disease-causing mutation. Founder effects raise local prevalence in certain groups, including Afrikaners in South Africa, Christian Lebanese, and French Canadians. Lifelong exposure produces visible signs, and the disease is characterized by high LDL levels, premature cardiovascular disease, and peripheral signs such as tendinous xanthoma, xanthelasma and corneal arcus.\n\nGallstones are a separate, non-vascular problem. Cholesterol gallstones form when bile becomes supersaturated with cholesterol relative to its bile salts and phospholipids, which normally keep the sterol dissolved in micelles and vesicles. Once the bile is supersaturated, cholesterol monohydrate crystals nucleate and grow, and gallbladder stasis and mucin secretion promote aggregation into stones. Most gallstones in Western populations are predominantly cholesterol-based.\n\nThe links between cholesterol metabolism and cancer and neurodegeneration remain less settled. Many tumour cells increase cholesterol synthesis and LDL uptake to supply membrane building blocks and signalling lipids, which has made the pathway a subject of study in oncology. Epidemiological studies have reported associations between statin use or circulating cholesterol and cancer incidence or outcomes, but the results are inconsistent and largely observational, and randomized trials have not established a clear protective or harmful effect. In the brain, cholesterol is synthesized mainly within the central nervous system, because the blood–brain barrier restricts the entry of circulating lipoproteins. The apolipoprotein E4 allele is the strongest common genetic risk factor for late-onset Alzheimer disease, and it affects brain lipid transport, but whether blood cholesterol levels in midlife cause dementia is still debated. The current evidence is best described as associative, and causal conclusions for these conditions are not yet firmly established."
    },
    {
      "heading": "Measurement and clinical guidelines",
      "text": "Standard lipid panel\n\nThe 2026 guideline, published in March 2026 in the Journal of the American College of Cardiology and Circulation, replaces and retires the 2018 AHA/ACC and multisociety guidelines on blood cholesterol management. Its measurement recommendations start with a basic lipid profile, which may be drawn fasting or nonfasting and sets baseline values for risk estimation and the decision to start lipid-lowering therapy. A fasting sample is favored when triglycerides are at least 400 mg/dL or when there is a family history of dyslipidemia, premature ASCVD, or a known triglyceride disorder.\n\nThe panel normally reports total cholesterol, LDL-C, HDL-C and triglycerides. Non-HDL-C, which is total cholesterol minus HDL-C and so counts every atherogenic particle carrying apolipoprotein B, is also reported; the guideline recommends reporting non-HDL-C for ASCVD risk assessment and for guiding the initiation and monitoring of lipid-lowering therapy. Apolipoprotein B is recommended to help diagnose lipid and lipoprotein disorders, and once LDL-C and non-HDL-C targets are met it can refine residual risk, particularly in people with triglycerides of 150 mg/dL or higher, diabetes, or LDL-C below 70 mg/dL (apoB testing can be useful to improve risk assessment and guide therapy).\n\nLipoprotein(a)\n\nThe most visible change in testing is for lipoprotein(a). Lp(a) should be measured at least once in adulthood. The guideline's view is that lifestyle changes minimally affect Lp(a) levels, so repeat testing is generally not needed. Reference points for risk are graded: a level near 125 nmol/L (about 50 mg/dL) indicates meaningful risk, and a level near 250 nmol/L (about 100 mg/dL) marks a substantially higher-risk group. In the 2018 guideline Lp(a) appeared only as a risk enhancer, without a testing recommendation.\n\nRisk estimation and treatment goals\n\nThe guideline applies a three-step \"CPR\" approach: calculate, personalize, reclassify, and reassess. Risk is now estimated with the PREVENT equations rather than the Pooled Cohort Equations, and 10-year and 30-year estimates are used for adults aged 30 to 79. In the borderline (3% to under 5%) and intermediate (5% to under 10%) 10-year categories, treating toward LDL-C below 100 mg/dL and non-HDL-C below 130 mg/dL is considered reasonable. For people at high 10-year risk, targets are tighter. The guideline anticipates a 30–49% LDL-C reduction in borderline and intermediate risk and at least 50% in high-risk patients.\n\nFor established atherosclerotic disease, the very-high-risk group should reach LDL-C below 55 mg/dL and non-HDL-C below 85 mg/dL, while patients who do not meet the very-high-risk definition target LDL-C below 70 mg/dL. Some critics note that the sub-55 mg/dL goal for patients with extensive coronary calcium rests mainly on observational event rates and extrapolation from secondary-prevention trials.\n\nAdvanced particle-size testing\n\nThe guideline does not endorse advanced lipoprotein profiling. Methods such as gradient gel electrophoresis, ultracentrifugation, nuclear magnetic resonance and ion mobility, which estimate subclasses or LDL particle size, are not recommended to estimate ASCVD risk and guide initiation of lipid-lowering therapy, and the guideline assigns this practice a \"no benefit\" classification."
    },
    {
      "heading": "Pharmacological control",
      "text": "Lipid-lowering drugs act at different points in cholesterol handling: synthesis in the liver, absorption from the gut, and clearance of LDL from the blood. Most of the evidence for them comes from large randomized trials that measured cardiovascular events, not only LDL levels.\n\nStatins\n\nStatins are the most widely used class. They compete with the natural substrate at the active site of HMG-CoA reductase, which slows the conversion of HMG-CoA to mevalonate and reduces the cholesterol the liver makes. Statins attenuate the intracellular levels of cholesterol by inhibiting the rate-limiting enzyme 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase.\n\nLower intracellular sterol also changes gene expression. The sterol-sensing transcription factor SREBP is released from the endoplasmic reticulum, moves to the nucleus and increases transcription of the LDL receptor gene (Reduction in intracellular cholesterol induces activation of a protease, causing release of sterol regulatory element binding proteins (SREBPs) from the endoplasmic reticulum.). More receptors on hepatocytes pull LDL out of the circulation. Statins also raise PCSK9 expression slightly, but this effect is outweighed by the rise in LDL receptors, so circulating LDL falls overall. Clinically, LDL reductions depend on the agent and dose; statin therapy produces substantial reductions in LDL cholesterol (approximately 18% to 55%, depending on agent potency and dose). Some effects beyond LDL lowering, sometimes called pleiotropic, are thought to arise from reduced isoprenylation of signalling proteins such as Ras, Rho and Rac, though their clinical significance remains debated.\n\nEzetimibe and bile acid sequestrants\n\nEzetimibe acts in the intestine. It binds the sterol transporter NPC1L1 on the enterocyte brush border and reduces the uptake of dietary and biliary cholesterol; its direct binding to NPC1L1 was established in knockout mouse studies. Added to a statin, it lowers LDL by roughly a further 20%. The pivotal outcome trial, IMPROVE-IT, randomized 18,144 patients with ACS to simvastatin 40 mg/d plus ezetimibe 10 mg/d or simvastatin alone. The combination reduced the primary composite endpoint, with a significant 6.4% reduced risk (relative), and the benefit appeared larger in patients with diabetes. Safety outcomes, including cancer, muscle and gallbladder events, did not differ between groups.\n\nBile acid sequestrants are resins that act in the gut lumen. Bile acids are bound and excreted rather than reabsorbed, so the liver draws on its cholesterol pool to make replacement bile acids and upregulates LDL receptors. Their LDL-lowering effect is moderate, and gastrointestinal side effects and interactions with co-administered drugs limit their use.\n\nPCSK9 inhibitors and newer agents\n\nPCSK9 binds LDL receptors and directs them toward degradation, so inhibiting it preserves receptor numbers. Evolocumab and alirocumab are monoclonal antibodies against PCSK9; these agents typically reduce LDL-C levels by approximately 50%. Evolocumab is given as a 140-mg subcutaneous injection once every 2 weeks or 420 mg monthly.\n\nThe FOURIER trial enrolled 27 564 patients with stable atherosclerotic disease receiving statin therapy, with a median follow-up of 2.2 years. Compared with placebo, evolocumab reduced the composite of cardiovascular death, myocardial infarction or stroke by about 20%. Inclisiran, a small interfering RNA that suppresses hepatic PCSK9 synthesis, is administered twice yearly (300 mg) after initial loading in the ORION program. Bempedoic acid, which acts upstream of HMG-CoA reductase on ATP citrate lyase, and further oral and other agents are in clinical use or development.\n\nTrial evidence, monitoring and safety\n\nThe evidence base differs across these drugs. Ezetimibe and PCSK9 inhibitors have outcome data from trials of several thousand patients, but many trial endpoints are composites, and their interpretation depends on adjudication. A later reanalysis of FOURIER reported that the cause of death adjudicated by the FOURIER clinical events committee differed from that declared by the local clinical investigator for 41.4% of deaths, a discrepancy that has been discussed in the literature.\n\nIn practice, lipid levels are usually rechecked a few weeks to a few months after starting or changing therapy. Statin monitoring focuses on muscle symptoms, since myopathy is the most common reason for discontinuation, and rare cases of rhabdomyolysis have been reported. Statins are also associated with a small increase in new-onset diabetes, mainly in people with existing risk factors. Liver enzyme elevations occur but are uncommon. Ezetimibe is generally well tolerated. PCSK9 antibodies cause mainly injection-site reactions, and their long-term safety and cost-effectiveness remain subjects of ongoing study."
    },
    {
      "heading": "Discovery and research history",
      "text": "Cholesterol entered the record through clinical material before it became a chemical problem. François Poulletier de la Salle is credited with first identifying cholesterol in solid form in gallstones in 1769, though other accounts give 1758 or 1784 for the first isolation from gallstones, so the early dates should be treated with caution. Michel Eugène Chevreul then made the decisive chemical step. In 1815 he reported the composition of gallstones and described a new fatty substance in the Annales de Chimie. His tests showed that the material could not be saponified, which ruled out treating it as a wax. The name he gave, cholesterine, came from Greek roots: chole for bile and stereos for solid. The \"-ol\" ending used today was adopted later, reflecting the molecule's classification as an alcohol.\n\nThe structural work of the early twentieth century was dominated by the German chemist Adolf Windaus. His research career began in 1901 and lasted about 30 years, and his first work was on cholesterol, about which almost nothing was known. He showed that cholesterol could be converted into a bile acid, cholanic acid, which demonstrated a close relationship between cholesterol and bile acids. His most influential line of work concerned vitamin D. In the course of this research he identified 7-dehydrocholesterol as a precursor of the vitamin. He also showed that sunlight cleaves a chemical bond in that precursor to produce the active vitamin, which explained why sun exposure can prevent rickets. Windaus received the 1928 Nobel Prize in Chemistry for his studies on the sterols and their connection with vitamins, the first award to mention vitamins. The complete ring framework of the sterol nucleus was established in 1932, which made it possible to determine the structures of many other biologically important sterols, including sex hormones and adrenocortical hormones.\n\nThe question of how the body makes cholesterol was answered in the 1950s and 1960s, largely through the work of Konrad Bloch and Feodor Lynen. The two worked generally separately over roughly a quarter of a century, and their findings led to the same conclusions. Their joint 1964 Nobel Prize in Physiology or Medicine recognized their discoveries concerning the mechanism and regulation of cholesterol and fatty acid metabolism. Lynen contributed a key chemical identification: in 1951 he determined the structure of acetyl-coenzyme A, the activated form of acetic acid that plays a central role in metabolism. Bloch used isotope labelling to trace the origin of the molecule. He traced all of the carbon atoms in cholesterol back to acetate. The method itself was borrowed from Rudolf Schoenheimer's laboratory, where radioisotopes were used as tracers to follow particular molecules through cells and living organisms. Some experiments used bread mold, because fungi also produce squalene, and Bloch had originally considered sharks, whose livers contain large amounts of squalene, as experimental animals. The resulting pathway, in which acetate is assembled into squalene and then converted into cholesterol, became the foundation for later work on the rate-limiting steps and their regulation.\n\nThe regulatory side of cholesterol biology was recognized by Michael Brown and Joseph Goldstein, who received the 1985 Nobel Prize in Physiology or Medicine for their work on controlling cholesterol metabolism. Their central discovery was the LDL receptor, which removes cholesterol-carrying particles from the blood and was described in the early 1970s. The sterol-sensing transcription pathway known as SREBP, which links sterol levels in the endoplasmic reticulum to gene expression, was characterized in the early 1990s, after the prize was awarded, so the 1985 recognition is mainly associated with the receptor work. The importance of this research is reflected in the scale of recognition overall: a review counted thirteen Nobel Prizes awarded to scientists who devoted major parts of their careers to cholesterol research."
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    {
      "title": "Cholesterol",
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    }
  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}