Cholesterol

What cholesterol is for

Cholesterol is a fat-like molecule that human cells need for their membranes and that the body converts into steroid hormones, bile acids and vitamin D ¹².

Synthesis: the mevalonate pathway

Cells build cholesterol from acetyl-CoA, a two-carbon unit, in more than 30 enzymatic reactions ¹².

Mevalonate pathwayCytosol and endoplasmic reticulum

Acetyl-CoA
Acetyl-CoA acetyltransferase 2 (ACAT2)Condenses two acetyl-CoA and releases CoA
Acetoacetyl-CoA
HMG-CoA synthase 1 (HMGCS1)Acetyl-CoA, H2OAdds a third acetyl unit and releases CoA
HMG-CoA
HMG-CoA reductase (HMGCR)2 NADPHStatinsRate-limiting step; enzyme of the ER membrane; releases CoA
Mevalonate
Mevalonate kinase (MVK)ATP
Mevalonate 5-phosphate
Phosphomevalonate kinase (PMVK)ATP
Mevalonate 5-diphosphate
Diphosphomevalonate decarboxylase (MVD)ATPReleases CO2 and phosphate; product is the C5 isoprenoid unit
Isopentenyl diphosphate
Isopentenyl-diphosphate isomerase 1 (IDI1)
Dimethylallyl diphosphate
Farnesyl diphosphate synthase (FDPS)Isopentenyl diphosphateAdds one C5 unit and releases diphosphate
Geranyl diphosphate
Farnesyl diphosphate synthase (FDPS)Isopentenyl diphosphateBranch point to ubiquinone, dolichol, haem A and prenylated proteins
Farnesyl diphosphate
Squalene synthase (FDFT1)NADPHJoins two farnesyl diphosphates through presqualene diphosphate
Squalene
Squalene monooxygenase (SQLE)O2, NADPH through cytochrome P450 oxidoreductase (POR), FADAlso regarded as rate-limiting for sterol synthesis
(S)-2,3-Epoxysqualene
Lanosterol synthase (LSS)Cyclisation yields the first sterol
Lanosterol
several stepsBloch or modified Kandutsch-Russell route; CYP51A1 first, DHCR24 or DHCR7 last
Cholesterol

HMG-CoA reductase, an enzyme of the endoplasmic reticulum (ER) membrane, catalyses the rate-limiting step ³⁴. Statins inhibit this reaction ³.

Sterol sensing: SREBP-2, SCAP and INSIG

Cells switch the genes for cholesterol synthesis and uptake on or off according to the cholesterol content of an internal membrane, the ER ⁵⁴.

When ER cholesterol is low, SCAP transports the transcription factor SREBP-2 to the Golgi ⁴. There, two proteases release a domain of SREBP-2 that activates the genes for the LDL receptor and the biosynthetic enzymes ⁴¹. When ER cholesterol rises, SCAP binds cholesterol and INSIG, and the complex stays in the ER ⁴. In Chinese hamster ovary cells, SREBP-2 processing fell abruptly once ER cholesterol exceeded about 5 mol% of ER lipids ⁵. In a model based on hamster and mouse experiments, statins lower hepatic ER cholesterol, activate SREBP-2, raise LDL receptors and lower plasma LDL ¹.

Uptake: the LDL receptor

Cholesterol travels in the blood mainly inside low-density lipoprotein (LDL) particles, which cells take up through a surface receptor ¹³.

Hepatic receptors clear most LDL ¹. Heterozygotes for familial hypercholesterolaemia have half the functional receptors and about twice the normal LDL ¹.

PCSK9

PCSK9, a protein released by the liver, lowers the number of LDL receptors on liver cells and so raises blood LDL ¹⁶.

PCSK9 binds the LDL receptor, which is then degraded instead of returning to the cell surface ⁶¹³. African Americans heterozygous for the nonsense mutation Y142X or C679X had 28% lower LDL and an 88% reduction in heart attacks ¹.

Absorption: NPC1L1

Cells lining the small intestine absorb part of the cholesterol in the gut through a membrane protein, NPC1L1 ⁴³.

Disposal: bile acids and reverse cholesterol transport

Most tissues cannot break cholesterol down ⁷. In reverse cholesterol transport, it returns on high-density lipoprotein (HDL) to the liver ⁷. The liver secretes it into bile unchanged or as bile acids ⁷.

Conversion to bile acids accounts for about 90% of cholesterol breakdown ⁸. Cholesterol 7α-hydroxylase (CYP7A1) catalyses the first and rate-limiting step of the classic pathway ⁸³. Bile acid-binding resins increase faecal bile acid excretion and lower plasma cholesterol ⁸; see bile acid sequestrants.

References

Independent research
Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins Cell, 2015.
doi:10.1016/j.cell.2015.01.036 PubMed 25815993
Funding and finding
Funding
The authors' experimental work over 40 years was supported by grants from the NIH (HL-20948), the Perot Foundation, the Moss Heart Foundation and the O'Donnell Foundation.
Finding
Narrative review. Cholesterol is a 27-carbon, four-ring molecule synthesised from acetate, a two-carbon unit attached to CoA; HMG-CoA reductase catalyses the rate-controlling step. An LDL particle contains about 1500 cholesteryl ester molecules in its core and a coat of about 800 phospholipid molecules, about 500 unesterified cholesterol molecules and one 500-kDa apoB. LDL receptors cluster in coated pits; internalised LDL reaches lysosomes, where cholesteryl esters are hydrolysed. The LDLR gene on the short arm of chromosome 19 has 18 exons and encodes a mature protein of 839 amino acids with seven cysteine-rich LDL-binding repeats and a 50-amino-acid cytoplasmic tail that directs it to coated pits. FH heterozygotes have half the functional receptors and about twofold LDL. Nuclear SREBP-2 activates the LDL receptor gene and the cholesterol biosynthetic genes; statins lower ER cholesterol, activate SREBP-2, raise hepatic LDL receptors and lower plasma LDL. Most LDL is removed by hepatic LDL receptors. PCSK9 binds hepatic LDL receptors and disrupts their recycling. African-Americans heterozygous for PCSK9 nonsense mutations Y142X or C679X had 28% lower LDL and 88% fewer heart attacks. Conclusions on human liver are extrapolated from rats, mice, hamsters and dogs.
Independent research
Mitsche MA, McDonald JG, Hobbs HH, Cohen JC. Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways eLife, 2015.
doi:10.7554/eLife.07999 PubMed 26114596
Funding and finding
Funding
Howard Hughes Medical Institute; National Institutes of Health (R37HL72304, PO1 HL20948, K01GM109317, UL1TR001105); Clayton Foundation for Research. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Finding
Cholesterol is synthesised from acetate through more than 30 enzymatic reactions grouped into condensation of acetate to isoprene, polymerisation of isoprene to squalene, cyclisation of squalene to lanosterol and conversion of lanosterol to cholesterol. The Bloch and Kandutsch-Russell pathways differ in the stage at which the side-chain Delta-24 double bond is reduced: last, by DHCR24 acting on desmosterol, in the Bloch pathway; at lanosterol, with conversion via 7-dehydrocholesterol, in the Kandutsch-Russell pathway. No mouse tissue used the canonical Kandutsch-Russell pathway; tissues used a hybrid, the modified Kandutsch-Russell pathway, in which intermediates follow the Bloch pathway until demethylation of the sterol nucleus is complete and then undergo Delta-24 reduction. Proportional flux through the Bloch pathway ranged from 8% in preputial gland to 97% in testes. The route by which cholesterol travels from peripheral tissues to the liver, termed reverse cholesterol transport, remains to be fully defined.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute [HG002273]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.
Finding
Reviewed UniProtKB entries, release 2026_03, read through rest.uniprot.org. HMGCR (P04035): converts HMG-CoA to mevalonate, the rate-limiting step in the synthesis of cholesterol and other isoprenoids; ER membrane; main target of statins. FDFT1 (P37268): joins two farnesyl diphosphates through presqualene diphosphate with NADPH or NADH; first committed enzyme of sterol synthesis. SQLE (Q14534): oxidises squalene to (S)-2,3-epoxysqualene; considered a rate-limiting enzyme. FDPS (P14324): forms farnesyl diphosphate, precursor of sterols, dolichols and ubiquinones and substrate for protein farnesylation and geranylgeranylation. GGPS1 (O95749): forms geranylgeranyl diphosphate. PDSS1 (Q5T2R2) and PDSS2 (Q86YH6): extend farnesyl diphosphate with isopentenyl diphosphate to the decaprenyl side chain of ubiquinone-10; mitochondrion. COQ2 (Q96H96): prenylates 4-hydroxybenzoate with the polyprenyl chain; in humans the product is CoQ10, which transports electrons between respiratory chain complexes. DHDDS (Q86SQ9) and NUS1 (Q96E22): condense isopentenyl diphosphate onto farnesyl diphosphate to dehydrodolichyl diphosphate, mostly C95 and C100, precursor of dolichol phosphate, the sugar carrier for ER protein glycosylation. SRD5A3 (Q9H8P0): polyprenal reductase in the conversion of polyprenol to dolichol. FNTA (P49354), FNTB (P49356) and PGGT1B (P53609): transfer a farnesyl or geranylgeranyl group to the cysteine fourth from the C-terminus of proteins ending in Cys-aliphatic-aliphatic-X. LDLR (P01130): binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis; receptor-ligand complexes first cluster into clathrin-coated pits. PCSK9 (Q8NBP7): binds LDLR and promotes its degradation in intracellular acidic compartments by a non-proteolytic mechanism. NPC1L1 (Q9UHC9): critical for cholesterol uptake across the enterocyte plasma membrane; apical membrane. CYP7A1 (P22680): 7-alpha-hydroxylates cholesterol, a rate-limiting step of bile acid synthesis, with electrons from NADPH through cytochrome P450 reductase; ER membrane. FGF19 (O95750): suppresses bile acid synthesis by down-regulating CYP7A1; activity requires KLB and FGFR4. Gene-to-protein assignments of reviewed human entries: SREBF2 SREBP-2 (Q12772); SCAP (Q12770); INSIG1 (O15503); INSIG2 (Q9Y5U4); MBTPS1 site-1 protease (Q14703); MBTPS2 site-2 protease (O43462); LIPA lysosomal acid lipase (P38571); NPC1 (O15118); STAR (P49675); CYP11A1 cholesterol side-chain cleavage enzyme (P05108); CYP27B1 25-hydroxyvitamin D 1-alpha-hydroxylase (O15528); CYP27A1 sterol 27-hydroxylase (Q02318); CYP7B1 oxysterol 7-alpha-hydroxylase (O75881); NR1H4 farnesoid X receptor (Q96RI1); NR0B2 small heterodimer partner (Q15466); POR NADPH-cytochrome P450 reductase (P16435); APOA1 (P02647); ABCG1 (P45844); LIPG endothelial lipase (Q9Y5X9); DHCR24 (Q15392); DHCR7 (Q9UBM7).
Independent research
Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on Cholesterol Homeostasis: The Central Role of Scap Annual Review of Biochemistry, 2018.
doi:10.1146/annurev-biochem-062917-011852 PubMed 28841344
Funding and finding
Funding
National Institutes of Health (HL20948 to J.L.G., M.S.B. and A.R.) and The Welch Foundation (I-1793 to A.R.).
Finding
Review. SREBPs are ER membrane proteins with an NH2-terminal bHLH-Zip domain, two transmembrane helices and a COOH-terminal domain that binds Scap; SREBP-2 is specialised for cholesterol homeostasis. In cholesterol-deprived cells the MELADL sequence in cytosolic Loop 6 of Scap binds Sec23-Sec24 of COPII and Scap carries SREBPs to the Golgi, where S1P cleaves the luminal loop and S2P cleaves within the transmembrane helix, releasing the bHLH-Zip domain to the nucleus. Cholesterol binds luminal Loop 1 of Scap (apparent Kd 67 nM for the purified loop); Scap then binds Insig-1 or Insig-2 and MELADL becomes inaccessible to COPII. 25-Hydroxycholesterol binds Insig, not Scap. Insig-1 and Insig-2 also bind the membrane domain of HMG CoA reductase, the rate-controlling enzyme of cholesterol biosynthesis, and trigger its ubiquitination and degradation. Sterol-sensing domains occur in Scap, HMG CoA reductase, 7-dehydrocholesterol reductase (last step of cholesterol synthesis), NPC1 (export of LDL-derived cholesterol from lysosomes) and NPC1L1 (intestinal cholesterol absorption).
Independent research
Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance Cell Metabolism, 2008.
doi:10.1016/j.cmet.2008.10.008 PubMed 19041766
Funding and finding
Funding
Grants from the NIH (HL20948 and GM069338) and the Perot Family Foundation.
Finding
In purified ER membranes of CHO cells, resting ER cholesterol was about 7 mol% of ER lipids and whole-cell cholesterol about 35 mol% of cell lipids. SREBP-2 processing fell abruptly when ER cholesterol exceeded about 5 mol%; 50% inhibition occurred at 4.5 mol% (Hill coefficient 3.7) with cholesterol-cyclodextrin and at 5.7 mol% (Hill coefficient 3.5) with beta-VLDL in CHO-K1 cells, and at 5.5 mol% (Hill coefficient 5.1) in CHO-7 cells; the authors summarise the switch as 4.5-5.7 mol% with Hill coefficients of 3.5-5.1. About 6-fold overexpression of Insig-1 lowered the 50% inhibition point from 5.5 to 3.1 mol% and raised the Hill coefficient from 5.1 to 6.9.
Independent research
Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice Journal of Clinical Investigation, 2006.
doi:10.1172/JCI29383 PubMed 17080197
Funding and finding
Funding
Grants from the Perot Family Foundation and the NIH (HL-20948 and HL-38049); T.A. Lagace held a fellowship from the Natural Sciences and Engineering Research Council of Canada; D.E. Curtis was supported by the UT Southwestern Physician Scientist Training Program.
Finding
PCSK9 undergoes autocatalytic cleavage in the ER; the cleaved prodomain stays associated with the catalytic domain and the complex is secreted. PCSK9 was independently identified as an SREBP-regulated gene. Plasma PCSK9 in 72 volunteers ranged from about 50 to about 600 ng/ml. In HepG2 cells, 0.5 micrograms per ml purified PCSK9 for 4 hours reduced cell-surface LDL receptors by about 50%; the gain-of-function mutant D374Y was at least 10-fold more active. Uptake of PCSK9 depended largely on LDL receptors; PCSK9 and the receptor associated directly and colocalised in late endocytic compartments. In parabiosed mice, PCSK9 from transgenic partners reduced hepatic LDL receptors of wild-type mice to nearly undetectable levels.
Independent research
Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis Journal of Lipid Research, 2009.
doi:10.1194/jlr.R800088-JLR200 PubMed 19064999
Funding and finding
Funding
P01-HL22633 from the NHLBI.
Finding
Review. Most peripheral cells cannot catabolise cholesterol and dispose of it by efflux to extracellular acceptors such as HDL. ABCA1 mediates efflux to lipid-poor apoA-I and ABCG1 efflux to mature HDL; LCAT esterifies HDL cholesterol; HDL cholesterol reaches the liver directly through SR-BI or after CETP-mediated transfer to apoB-containing lipoproteins and uptake by the LDL receptor; hepatic cholesterol is excreted into bile as cholesterol or after conversion to bile acids. Rodents lack CETP. A tracer study in healthy humans suggested that almost all HDL-derived labelled cholesterol excreted into bile was first transferred to apoB-containing lipoproteins. In animals, the rate of macrophage reverse cholesterol transport is more strongly associated with atherosclerosis than steady-state HDL cholesterol; methods to measure it in humans were still being developed and validated.
Independent research
Russell DW. Fifty years of advances in bile acid synthesis and metabolism Journal of Lipid Research, 2009.
doi:10.1194/jlr.R800026-JLR200 PubMed 18815433
Funding and finding
Funding
National Institutes of Health Grants P01 HL-20948 and PL1 DK-81182, the Robert A. Welch Foundation (I-0971) and the Perot Family Fund.
Finding
Review. Conversion of cholesterol to bile acids in the liver accounts for about 90% of cholesterol breakdown; steroid hormones, oxysterols and vitamin D account for less than 10%. At least 16 enzymes catalyse up to 17 reactions from cholesterol to a conjugated bile salt; CYP7A1 catalyses the initiating and rate-limiting step; an alternate pathway begins with side-chain hydroxylation followed by oxysterol 7-alpha-hydroxylation. Solubility rises from about 4 micrograms per litre for cholesterol to about 670 g per litre for a conjugated bile salt. A conjugated bile salt may pass through the enterohepatic circulation 4 to 12 times a day. Bile acids repress CYP7A1 through FXR, which induces SHP, and through intestinal FGF15 acting on hepatic FGFR4 and beta-Klotho. Bile acid binding resins such as cholestyramine and colesevelam increase faecal bile acid excretion and lower plasma cholesterol. In skin, UV light cleaves 7-dehydrocholesterol to previtamin D, which rearranges to vitamin D3; the liver 25-hydroxylates it and the kidney 1-alpha-hydroxylates it through CYP27B1.
Industry-funded
Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1) Proceedings of the National Academy of Sciences of the United States of America, 2005.
doi:10.1073/pnas.0500269102 PubMed 15928087
Funding and finding
Funding
not stated
Finding
Labelled ezetimibe glucuronide bound a single site in intestinal brush-border membranes and in HEK 293 cells expressing NPC1L1; binding affinities of ezetimibe and analogues to recombinant NPC1L1 matched those of native enterocyte membranes. Dissociation constants of ezetimibe glucuronide were 12,000, 540, 40 and 220 nM for mouse, rat, rhesus monkey and human NPC1L1. Ezetimibe did not bind membranes from NPC1L1-knockout mice.
Industry-funded
Myocardial Infarction Genetics Consortium Investigators, Stitziel NO, Won HH, Morrison AC, Peloso GM, Do R, et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease New England Journal of Medicine, 2014.
doi:10.1056/NEJMoa1405386 PubMed 25390462
Funding and finding
Participants
113,094
Funding
NHLBI grants K08HL114642, T32HL007208, R01HL107816, RC2HL102926 and RC2HL102925; NHGRI grant 5U54HG003067-11; the Foundation for Barnes-Jewish Hospital; a Banting Fellowship from the Canadian Institutes of Health Research; a grant from the Donovan Family Foundation, an investigator-initiated research grant from Merck and a grant from Fondation Leducq (all to S. Kathiresan). Funders of the contributing studies are listed in the Supplementary Appendix.
Finding
Sequencing of NPC1L1 in 7364 patients with coronary heart disease and 14,728 controls identified 15 inactivating mutations; about 1 in 650 persons was a heterozygous carrier. Carriers had LDL cholesterol 12 mg/dl (0.31 mmol/l) lower than non-carriers (P = 0.04) and a 53% lower risk of coronary heart disease (odds ratio 0.47, 95% CI 0.25 to 0.87). Overall, 11 of 29,954 patients (0.04%) and 71 of 83,140 controls (0.09%) carried an inactivating mutation. The study states that ezetimibe lowers LDL cholesterol by inhibiting NPC1L1.
Expert consensus
Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel European Heart Journal, 2017.
doi:10.1093/eurheartj/ehx144 PubMed 28444290
Funding and finding
Funding
Travel and meeting logistics were supported by unrestricted educational grants from MSD and Amgen to the European Atherosclerosis Society; the companies were not present at the Consensus Panel meetings, had no role in the design or content of the manuscript and had no right to approve or disapprove the final document. The European Atherosclerosis Society paid the open-access charges.
Finding
Meta-analyses of over 200 prospective cohort studies, Mendelian randomisation studies and randomised trials, including more than 2 million participants, over 20 million person-years of follow-up and over 150,000 cardiovascular events, show a consistent dose-dependent log-linear association between the absolute magnitude of exposure to LDL cholesterol and the risk of atherosclerotic cardiovascular disease, which appears to increase with the duration of exposure. The panel concluded that LDL causes atherosclerotic cardiovascular disease.
Industry-funded
Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study Lancet, 2012.
doi:10.1016/S0140-6736(12)60312-2 PubMed 22607825
Funding and finding
Funding
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation and the German Federal Ministry of Education and Research. The sponsors had no role in the conduct or interpretation of the study. Data collection in the contributing Dortmund Health Study was supported by the German Migraine and Headache Society and by unrestricted grants from AstraZeneca, Berlin Chemie, Boots Healthcare, GlaxoSmithKline, McNeil Pharma, MSD Sharp and Dohme and Pfizer to the University of Muenster.
Finding
Carriers of the LIPG 396Ser allele (2.6% frequency) had HDL cholesterol 0.14 mmol/l higher and similar other risk factors; the expected odds ratio for myocardial infarction was 0.87 (95% CI 0.84 to 0.91), but the observed odds ratio was 0.99 (0.88 to 1.11; P = 0.85). A 1 SD genetic increase in HDL cholesterol from a 14-SNP score was not associated with myocardial infarction (odds ratio 0.93, 0.68 to 1.26), whereas a 1 SD genetic increase in LDL cholesterol was (odds ratio 2.13, 1.69 to 2.69).
Industry-funded
Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL cholesterol efflux capacity and incident cardiovascular events New England Journal of Medicine, 2014.
doi:10.1056/NEJMoa1409065 PubMed 25404125
Funding and finding
Participants
2,924
Follow-up
median 9.4 years
Funding
Grants from the Donald W. Reynolds Foundation, the National Center for Advancing Translational Sciences of the NIH (UL1TR001105), the NHLBI (K08HL1813) and the American Heart Association (12SDG11900066), and a research grant from the Investigator Studies Program of Merck Sharp and Dohme. Merck Sharp and Dohme had no role in the design of the study, in the collection or analysis of the data, in the writing of the manuscript or in the decision to submit it.
Finding
Baseline HDL cholesterol was not associated with atherosclerotic cardiovascular events after adjustment (hazard ratio 1.08, 95% CI 0.59 to 1.99). The primary end point occurred in 132 of 2416 participants: 49 of 602 (8.1%) in the lowest and 22 of 602 (3.7%) in the highest quartile of cholesterol efflux capacity; the fully adjusted hazard ratio for the highest versus lowest quartile was 0.33 (0.19 to 0.55), a 67% lower risk.

Updated 2026-10-21