Table Info

Table 1.

Summary of cholesterol synthesis in brain cell subtypes

Cell type	Subtypes	Function of cell	Function of cholesterol	Cholesterol synthesis	K-R or Bloch pathway?
Neurons	Subtypes many^*	Processing and transmission of cellular signals	Regulates membrane fluidity, required for cell membranes and myelin sheaths [29]. Present in lipid rafts and facilitates ion channel function, neuron receptor localization, neurotransmitter transport, and cellular growth and development [2, 26, 29].	High during embryonic development [28, 30]. Low during adulthood, when cholesterol is mainly sourced from astrocytes [26, 31].	Both [24, 28]
Glial cells	Astrocytes	Maintenance of CNS homeostasis, provision of biochemical and nutritional support to neurons and blood-brain barrier, synaptic transmission, immune function	Required for cell membrane fluidity regulation, lipid raft formation, and carbohydrate metabolism [32]. Cholesterol is exported to other brain cells [32, 33].	Low during embryonic development [28]. High after birth [26, 34].	Bloch [24]
	Oligodendrocytes	Synthesis and maintenance of myelin sheaths to insulate neuronal axons for faster signal transmission	Required for synthesis of myelin sheaths [35–37].	High after birth and in early childhood [9, 35]. Dynamic during adulthood. Cholesterol is sourced locally and from astrocytes [38, 39].	Possibly K-R [24] but requires further study
	Microglia	Brain macrophage; immune function and injury repair	Lipid composition modulates microglial function in phagocytosis, immune surveying, synapse pruning [33, 40, 41]. Desmosterol (cholesterol precursor) activates LXR signaling to resolve inflammation and promote oligodendrocyte maturation [42].	Synthesis rate low, sourced from astrocytes [43].	Possibly K-R [24] but requires further study

Note that many neuronal subtypes are present in the brain, but for the purpose of this review the main role of neurons and their cholesterol synthesis is discussed

Declarations

Acknowledgements

The authors thank members of the Brown laboratory for their intellectural assistance to this review.

Author contributions

AJB and ICG: funding acquisition and conceptualization. AJB, ICG, ABC, LQ: writing-original draft and editing. LQ and ABC: visualization and preparation of figures and tables. All authors approved the final version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the Australian Research Council Discovery Project Grant [DP170101178]. Amanda B. Chai and Lydia Qian are supported by an Australian Research Training Program scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Björkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol. 2004;24:806–15. [DOI] [PubMed]

Allen JA, Halverson-Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci. 2007;8:128–40. [DOI] [PubMed]

Gamba P, Staurenghi E, Testa G, Giannelli S, Sottero B, Leonarduzzi G. A crosstalk between brain cholesterol oxidation and glucose metabolism in Alzheimer’s disease. Front Neurosci. 2019;13:556. [DOI] [PubMed] [PMC]

Krause MR, Regen SL. The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts. Acc Chem Res. 2014;47:3512–21. [DOI] [PubMed]

Luu W, Sharpe LJ, Capell-Hattam I, Gelissen IC, Brown AJ. Oxysterols: old tale, new twists. Annu Rev Pharmacol Toxicol. 2016;56:447–67. [DOI] [PubMed]

Björkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med. 2006;260:493–508. [DOI] [PubMed]

Yang J, Wang L, Jia R. Role of de novo cholesterol synthesis enzymes in cancer. J Cancer. 2020;11:1761–7. [DOI] [PubMed] [PMC]

Liu M, Kuhel DG, Shen L, Hui DY, Woods SC. Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice. Am J Physiol Regul Integr Comp Physiol. 2012;303:R903–8. [DOI] [PubMed] [PMC]

Quan G, Xie C, Dietschy JM, Turley SD. Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Brain Res Dev Brain Res. 2003;146:87–98. [DOI] [PubMed]

10.

Andersson M, Elmberger PG, Edlund C, Kristensson K, Dallner G. Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices. FEBS Lett. 1990;269:15–8. [DOI] [PubMed]

11.

Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015;6:254–64. [DOI] [PubMed] [PMC]

12.

Valenza M, Marullo M, Di Paolo E, Cesana E, Zuccato C, Biella G, et al. Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease. Cell Death Differ. 2015;22:690–702. [DOI] [PubMed] [PMC]

13.

Gill S, Stevenson J, Kristiana I, Brown AJ. Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase. Cell Metab. 2011;13:260–73. [DOI] [PubMed]

14.

Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on cholesterol homeostasis: the central role of scap. Annu Rev Biochem. 2018;87:783–807. [DOI] [PubMed] [PMC]

15.

Courtney R, Landreth GE. LXR regulation of brain cholesterol: from development to disease. Trends Endocrinol Metab. 2016;27:404–14. [DOI] [PubMed] [PMC]

16.

Sharpe LJ, Coates HW, Brown AJ. Post-translational control of the long and winding road to cholesterol. J Biol Chem. 2020;295:17549–59. [DOI] [PubMed] [PMC]

17.

Engelking LJ, Cantoria MJ, Xu Y, Liang G. Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin Cell Dev Biol. 2018;81:98–109. [DOI] [PubMed] [PMC]

18.

Hong C, Duit S, Jalonen P, Out R, Scheer L, Sorrentino V, et al. The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. J Biol Chem. 2010;285:19720–6. [DOI] [PubMed] [PMC]

19.

Nelissen K, Mulder M, Smets I, Timmermans S, Smeets K, Ameloot M, et al. Liver X receptors regulate cholesterol homeostasis in oligodendrocytes. J Neurosci Res. 2012;90:60–71. [DOI] [PubMed]

20.

Feringa FM, van der Kant R. Cholesterol and Alzheimer’s disease; from risk genes to pathological effects. Front Aging Neurosci. 2021;13:690372. [DOI] [PubMed] [PMC]

21.

Nowaczyk MJM, Irons MB. Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet C Semin Med Genet. 2012;160C:250–62. [DOI] [PubMed]

22.

Pineda-Torra I, Siddique S, Waddington KE, Farrell R, Jury EC. Disrupted lipid metabolism in multiple sclerosis: a role for liver X receptors? Front Endocrinol (Lausanne). 2021;12:639757. [DOI] [PubMed] [PMC]

23.

Saito M, Benson EP, Saito M, Rosenberg A. Metabolism of cholesterol and triacylglycerol in cultured chick neuronal cells, glial cells, and fibroblasts: accumulation of esterified cholesterol in serum-free culture. J Neurosci Res. 1987;18:319–25. [DOI] [PubMed]

24.

Nieweg K, Schaller H, Pfrieger FW. Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem. 2009;109:125–34. [DOI] [PubMed]

25.

Pfrieger FW, Ungerer N. Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res. 2011;50:357–71. [DOI] [PubMed]

26.

van Deijk AF, Camargo N, Timmerman J, Heistek T, Brouwers JF, Mogavero F, et al. Astrocyte lipid metabolism is critical for synapse development and function in vivo. Glia. 2017;65:670–82. [DOI] [PubMed]

27.

Jansen M, Wang W, Greco D, Bellenchi GC, di Porzio U, Brown AJ, et al. What dictates the accumulation of desmosterol in the developing brain? FASEB J. 2013;27:865–70. [DOI] [PubMed]

28.

Genaro-Mattos TC, Anderson A, Allen LB, Korade Z, Mirnics K. Cholesterol biosynthesis and uptake in developing neurons. ACS Chem Neurosci. 2019;10:3671–81. [DOI] [PubMed] [PMC]

29.

Tracey TJ, Steyn FJ, Wolvetang EJ, Ngo ST. Neuronal lipid metabolism: multiple pathways driving functional outcomes in health and disease. Front Mol Neurosci. 2018;11:10. [DOI] [PubMed] [PMC]

30.

Saito K, Dubreuil V, Arai Y, Wilsch-Bräuninger M, Schwudke D, Saher G, et al. Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis. Proc Natl Acad Sci U S A. 2009;106:8350–5. [DOI] [PubMed] [PMC]

31.

Fünfschilling U, Saher G, Xiao L, Möbius W, Nave KA. Survival of adult neurons lacking cholesterol synthesis in vivo. BMC Neurosci. 2007;8:1. [DOI] [PubMed] [PMC]

32.

Lee JA, Hall B, Allsop J, Alqarni R, Allen SP. Lipid metabolism in astrocytic structure and function. Semin Cell Dev Biol. 2021;112:123–36. [DOI] [PubMed]

33.

Barber CN, Raben DM. Lipid metabolism crosstalk in the brain: glia and neurons. Front Cell Neurosci. 2019;13:212. [DOI] [PubMed] [PMC]

34.

Ferris HA, Perry RJ, Moreira GV, Shulman GI, Horton JD, Kahn CR. Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci U S A. 2017;114:1189–94. [DOI] [PubMed] [PMC]

35.

Muse ED, Jurevics H, Toews AD, Matsushima GK, Morell P. Parameters related to lipid metabolism as markers of myelination in mouse brain. J Neurochem. 2001;76:77–86. [DOI] [PubMed]

36.

Saher G, Stumpf SK. Cholesterol in myelin biogenesis and hypomyelinating disorders. Biochim Biophys Acta. 2015;1851:1083–94. [DOI] [PubMed]

37.

Williamson JM, Lyons DA. Myelin dynamics throughout life: an ever-changing landscape? Front Cell Neurosci. 2018;12:424. [DOI] [PubMed] [PMC]

38.

Saher G, Brügger B, Lappe-Siefke C, Möbius W, Tozawa R, Wehr MC, et al. High cholesterol level is essential for myelin membrane growth. Nat Neurosci. 2005;8:468–75. [DOI] [PubMed]

39.

Werkman IL, Kövilein J, de Jonge JC, Baron W. Impairing committed cholesterol biosynthesis in white matter astrocytes, but not grey matter astrocytes, enhances in vitro myelination. J Neurochem. 2021;156:624–41. [DOI] [PubMed] [PMC]

40.

Loving BA, Bruce KD. Lipid and lipoprotein metabolism in microglia. Front Physiol. 2020;11:393. [DOI] [PubMed] [PMC]

41.

Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8. [DOI] [PubMed]

42.

Berghoff SA, Spieth L, Sun T, Hosang L, Schlaphoff L, Depp C, et al. Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. Nat Neurosci. 2021;24:47–60. [DOI] [PubMed] [PMC]

43.

Bohlen CJ, Bennett FC, Tucker AF, Collins HY, Mulinyawe SB, Barres BA. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron. 2017;94:759–73.e8. [DOI] [PubMed] [PMC]

44.

Valdez CM, Smith MA, Perry G, Phelix CF, Santamaria F. Cholesterol homeostasis markers are localized to mouse hippocampal pyramidal and granule layers. Hippocampus. 2010;20:902–5. [DOI] [PubMed] [PMC]

45.

Pfrieger FW. Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays. 2003;25:72–8. [DOI] [PubMed]

46.

Ohashi K, Osuga J, Tozawa R, Kitamine T, Yagyu H, Sekiya M, et al. Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. J Biol Chem. 2003;278:42936–41. [DOI] [PubMed]

47.

Tozawa R, Ishibashi S, Osuga J, Yagyu H, Oka T, Chen Z, et al. Embryonic lethality and defective neural tube closure in mice lacking squalene synthase. J Biol Chem. 1999;274:30843–8. [DOI] [PubMed]

48.

Mathews ES, Appel B. Cholesterol biosynthesis supports myelin gene expression and axon ensheathment through modulation of P13K/Akt/mTOR signaling. J Neurosci. 2016;36:7628–39. [DOI] [PubMed] [PMC]

49.

Vejux A, Ghzaiel I, Nury T, Schneider V, Charrière K, Sghaier R, et al. Oxysterols and multiple sclerosis: physiopathology, evolutive biomarkers and therapeutic strategy. J Steroid Biochem Mol Biol. 2021;210:105870. [DOI] [PubMed]

50.

Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M, Sen P, et al. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science. 2018;359:684–8. [DOI] [PubMed]

51.

Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020;23:194–208. [DOI] [PubMed] [PMC]

52.

Chen J, Zhang X, Kusumo H, Costa LG, Guizzetti M. Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis. Biochim Biophys Acta. 2013;1831:263–75. [DOI] [PubMed] [PMC]

53.

Wang H, Eckel RH. What are lipoproteins doing in the brain? Trends Endocrinol Metab. 2014;25:8–14. [DOI] [PubMed] [PMC]

54.

Camargo N, Goudriaan A, van Deijk AF, Otte WM, Brouwers JF, Lodder H, et al. Oligodendroglial myelination requires astrocyte-derived lipids. PLoS Biol. 2017;15:e1002605. [DOI] [PubMed] [PMC]

55.

Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron. 2016;91:328–40. [DOI] [PubMed]

56.

Mauch DH, Nägler K, Schumacher S, Göritz C, Müller EC, Otto A, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294:1354–7. [DOI] [PubMed]

57.

Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem. 2003;278:22980–8. [DOI] [PubMed]

58.

Flowers SA, Rebeck GW. APOE in the normal brain. Neurobiol Dis. 2020;136:104724. [DOI] [PubMed] [PMC]

59.

Frieden C, Garai K. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proc Natl Acad Sci U S A. 2012;109:8913–8. [DOI] [PubMed] [PMC]

60.

Frieden C, Wang H, Ho CMW. A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions. Proc Natl Acad Sci U S A. 2017;114:6292–7. [DOI] [PubMed] [PMC]

61.

Garai K, Baban B, Frieden C. Self-association and stability of the ApoE isoforms at low pH: implications for ApoE-lipid interactions. Biochemistry. 2011;50:6356–64. [DOI] [PubMed]

62.

Saito H, Dhanasekaran P, Baldwin F, Weisgraber KH, Lund-Katz S, Phillips MC. Lipid binding-induced conformational change in human apolipoprotein E. Evidence for two lipid-bound states on spherical particles. J Biol Chem. 2001;276:40949–54. [DOI] [PubMed]

63.

Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011;108:14813–8. [DOI] [PubMed] [PMC]

64.

Dong HK, Gim JA, Yeo SH, Kim HS. Integrated late onset Alzheimer’s disease (LOAD) susceptibility genes: cholesterol metabolism and trafficking perspectives. Gene. 2017;597:10–6. [DOI] [PubMed]

65.

Calero M, Tokuda T, Rostagno A, Kumar A, Zlokovic B, Frangione B, et al. Functional and structural properties of lipid-associated apolipoprotein J (clusterin). Biochem J. 1999;344:375–83. [DOI] [PubMed] [PMC]

66.

Rodríguez-Rivera C, Garcia MM, Molina-Álvarez M, González-Martín C, Goicoechea C. Clusterin: always protecting. Synthesis, function and potential issues. Biomed Pharmacother. 2021;134:111174. [DOI] [PubMed]

67.

Artemaki PI, Sklirou AD, Kontos CK, Liosi AA, Gianniou DD, Papadopoulos IN, et al. High clusterin (CLU) mRNA expression levels in tumors of colorectal cancer patients predict a poor prognostic outcome. Clin Biochem. 2020;75:62–9. [DOI] [PubMed]

68.

Ding X, Zhang W, Li S, Yang H. The role of cholesterol metabolism in cancer. Am J Cancer Res. 2019;9:219–27. [PubMed] [PMC]

69.

Debure L, Vayssiere JL, Rincheval V, Loison F, Le Drean Y, Michel D. Intracellular clusterin causes juxtanuclear aggregate formation and mitochondrial alteration. J Cell Sci. 2003;116:3109–21. [DOI] [PubMed]

70.

Herring SK, Moon HJ, Rawal P, Chhibber A, Zhao L. Brain clusterin protein isoforms and mitochondrial localization. Elife. 2019;8:e48255. [DOI] [PubMed] [PMC]

71.

Riwanto M, Rohrer L, Roschitzki B, Besler C, Mocharla P, Mueller M, et al. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation. 2013;127:891–904. [DOI] [PubMed]

72.

Gong JS, Kobayashi M, Hayashi H, Zou K, Sawamura N, Fujita SC, et al. Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice. J Biol Chem. 2002;277:29919–26. [DOI] [PubMed]

73.

Vance JE, Hayashi H. Formation and function of apolipoprotein E-containing lipoproteins in the nervous system. Biochim Biophys Acta. 2010;1801:806–18. [DOI] [PubMed]

74.

de Silva HV, Harmony JA, Stuart WD, Gil CM, Robbins J. Apolipoprotein J: structure and tissue distribution. Biochemistry. 1990;29:5380–9. [DOI] [PubMed]

75.

Gil SY, Youn BS, Byun K, Huang H, Namkoong C, Jang PG, et al. Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway. Nat Commun. 2013;4:1862. [DOI] [PubMed]

76.

Elliott DA, Weickert CS, Garner B. Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clin Lipidol. 2010;51:555–73. [DOI] [PubMed] [PMC]

77.

Orth M, Bellosta S. Cholesterol: its regulation and role in central nervous system disorders. Cholesterol. 2012;2012:292598. [DOI] [PubMed] [PMC]

78.

Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:8098–102. [DOI] [PubMed] [PMC]

79.

Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–18. [DOI] [PubMed] [PMC]

80.

Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci U S A. 2004;101:2070–5. [DOI] [PubMed] [PMC]

81.

Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, et al. Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and Abeta production. Neurobiol Dis. 2008;29:422–37. [DOI] [PubMed] [PMC]

82.

Chai AB, Lam HHJ, Kockx M, Gelissen IC. Apolipoprotein E isoform-dependent effects on the processing of Alzheimer’s amyloid-β. Biochim Biophys Acta Mol Cell Biol Lipids. 2021;1866:158980. [DOI] [PubMed]

83.

Wyatt AR, Yerbury JJ, Berghofer P, Greguric I, Katsifis A, Dobson CM, et al. Clusterin facilitates in vivo clearance of extracellular misfolded proteins. Cell Mol Life Sci. 2011;68:3919–31. [DOI] [PubMed]

84.

Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27:909–18. [DOI] [PubMed] [PMC]

85.

Su H, Rustam YH, Masters CL, Makalic E, McLean CA, Hill AF, et al. Characterization of brain-derived extracellular vesicle lipids in Alzheimer’s disease. J Extracell Vesicles. 2021;10:e12089. [DOI] [PubMed] [PMC]

86.

Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep. 2015;7:14. [DOI] [PubMed] [PMC]

87.

Kim WS, Guillemin GJ, Glaros EN, Lim CK, Garner B. Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells. Neuroreport. 2006;17:891–6. [DOI] [PubMed]

88.

Kim WS, Rahmanto AS, Kamili A, Rye KA, Guillemin GJ, Gelissen IC, et al. Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation. J Biol Chem. 2007;282:2851–61. [DOI] [PubMed]

89.

Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem. 2008;104:1145–66. [DOI] [PubMed]

90.

Fujiyoshi M, Ohtsuki S, Hori S, Tachikawa M, Terasaki T. 24S-hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical- and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression. J Neurochem. 2007;100:968–78. [DOI] [PubMed]

91.

Hartz AMS, Bauer B. ABC transporters in the CNS—an inventory. Curr Pharm Biotechnol. 2011;12:656–73. [DOI] [PubMed]

92.

Lin T, Islam O, Heese K. ABC transporters, neural stem cells and neurogenesis—a different perspective. Cell Res. 2006;16:857–71. [DOI] [PubMed]

93.

Vaughan AM, Oram JF. ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL. J Lipid Res. 2006;47:2433–43. [DOI] [PubMed]

94.

Matsuda A, Nagao K, Matsuo M, Kioka N, Ueda K. 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. J Neurochem. 2013;126:93–101. [DOI] [PubMed]

95.

Oram JF. HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol. Arterioscler Thromb Vasc Biol. 2003;23:720–7. [DOI] [PubMed]

96.

Warren MS, Zerangue N, Woodford K, Roberts LM, Tate EH, Feng B, et al. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. Pharmacol Res. 2009;59:404–13. [DOI] [PubMed]

97.

Sakai H, Tanaka Y, Tanaka M, Ban N, Yamada K, Matsumura Y, et al. ABCA2 deficiency results in abnormal sphingolipid metabolism in mouse brain. J Biol Chem. 2007;282:19692–9. [DOI] [PubMed]

98.

Calpe-Berdiel L, Zhao Y, de Graauw M, Ye D, van Santbrink PJ, Mommaas AM, et al. Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice. Atherosclerosis. 2012;223:332–41. [DOI] [PubMed]

99.

Davis W Jr. The ATP-binding cassette transporter-2 (ABCA2) regulates cholesterol homeostasis and low-density lipoprotein receptor metabolism in N2a neuroblastoma cells. Biochim Biophys Acta. 2011;1811:1152–64. [DOI] [PubMed] [PMC]

100.

Ban N, Matsumura Y, Sakai H, Takanezawa Y, Sasaki M, Arai H, et al. ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J Biol Chem. 2007;282:9628–34. [DOI] [PubMed]

101.

Fitzgerald ML, Xavier R, Haley KJ, Welti R, Goss JL, Brown CE, et al. ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J Lipid Res. 2007;48:621–32. [DOI] [PubMed]

102.

Cheong N, Madesh M, Gonzales LW, Zhao M, Yu K, Ballard PL, et al. Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome. J Biol Chem. 2006;281:9791–800. [DOI] [PubMed]

103.

Ikeda Y, Abe-Dohmae S, Munehira Y, Aoki R, Kawamoto S, Furuya A, et al. Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release. Biochem Biophys Res Commun. 2003;311:313–8. [DOI] [PubMed]

104.

Wang N, Lan D, Gerbod-Giannone M, Linsel-Nitschke P, Jehle AW, Chen W, et al. ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. J Biol Chem. 2003;278:42906–12. [DOI] [PubMed]

105.

Chan SL, Kim WS, Kwok JB, Hill AF, Cappai R, Rye KA, et al. ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem. 2008;106:793–804. [DOI] [PubMed]

106.

Matsumoto N, Kitayama H, Kitada M, Kimura K, Noda M, Ide C. Isolation of a set of genes expressed in the choroid plexus of the mouse using suppression subtractive hybridization. Neuroscience. 2003;117:405–15. [DOI] [PubMed]

107.

Trigueros-Motos L, van Capelleveen JC, Torta F, Castaño D, Zhang LH, Chai EC, et al. ABCA8 regulates cholesterol efflux and high-density lipoprotein cholesterol levels. Arterioscler Thromb Vasc Biol. 2017;37:2147–55. [DOI] [PubMed]

108.

Kooij G, van Horssen J, Bandaru VV, Haughey NJ, de Vries HE. The role of ATP-binding cassette transporters in neuro-inflammation: relevance for bioactive lipids. Front Pharmacol. 2012;3:74. [DOI] [PubMed] [PMC]

109.

Mahringer A, Fricker G. ABC transporters at the blood-brain barrier. Expert Opin Drug Metab Toxicol. 2016;12:499–508. [DOI] [PubMed]

110.

Neumann J, Rose-Sperling D, Hellmich UA. Diverse relations between ABC transporters and lipids: an overview. Biochim Biophys Acta Biomembr. 2017;1859:605–18. [DOI] [PubMed]

111.

Pohl A, Lage H, Müller P, Pomorski T, Herrmann A. Transport of phosphatidylserine via MDR1 (multidrug resistance 1)P-glycoprotein in a human gastric carcinoma cell line. Biochem J. 2002;365:259–68. [DOI] [PubMed] [PMC]

112.

van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 1996;87:507–17. [DOI] [PubMed]

113.

Garrigues A, Escargueil AE, Orlowski S. The multidrug transporter, P-glycoprotein, actively mediates cholesterol redistribution in the cell membrane. Proc Natl Acad Sci U S A. 2002;99:10347–52. [DOI] [PubMed] [PMC]

114.

Le Goff W, Settle M, Greene DJ, Morton RE, Smith JD. Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis. J Lipid Res. 2006;47:51–8. [DOI] [PubMed]

115.

Eckford PDW, Sharom FJ. The reconstituted P-glycoprotein multidrug transporter is a flippase for glucosylceramide and other simple glycosphingolipids. Biochem J. 2005;389:517–26. [DOI] [PubMed] [PMC]

116.

Beck K, Hayashi K, Dang K, Hayashi M, Boyd CD. Analysis of ABCC6 (MRP6) in normal human tissues. Histochem Cell Biol. 2005;123:517–28. [DOI] [PubMed]

117.

Ibold B, Tiemann J, Faust I, Ceglarek U, Dittrich J, Gorgels TGMF, et al. Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice. Sci Rep. 2021;11:2137. [DOI] [PubMed] [PMC]

118.

Fourcade S, Ruiz M, Camps C, Schlüter A, Houten SM, Mooyer PAW, et al. A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis. Am J Physiol Endocrinol Metab. 2009;296:E211–21. [DOI] [PubMed]

119.

Kawaguchi K, Morita M. ABC transporter subfamily D: distinct differences in behavior between ABCD1–3 and ABCD4 in subcellular localization, function, and human disease. Biomed Res Int. 2016;2016:6786245. [DOI] [PubMed] [PMC]

120.

Wang N, Yvan-Charvet L, Lütjohann D, Mulder M, Vanmierlo T, Kim TW, et al. ATP-binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J. 2008;22:1073–82. [DOI] [PubMed]

121.

Burgess BL, Parkinson PF, Racke MM, Hirsch-Reinshagen V, Fan J, Wong C, et al. ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. J Lipid Res. 2008;49:1254–67. [DOI] [PubMed]

122.

Kobayashi A, Takanezawa Y, Hirata T, Shimizu Y, Misasa K, Kioka N, et al. Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1. J Lipid Res. 2006;47:1791–802. [DOI] [PubMed]

123.

Xu M, Zhou H, Tan KCB, Guo R, Shiu SWM, Wong Y. ABCG1 mediated oxidized LDL-derived oxysterol efflux from macrophages. Biochem Biophys Res Commun. 2009;390:1349–54. [DOI] [PubMed]

124.

Dodacki A, Wortman M, Saubaméa B, Chasseigneaux S, Nicolic S, Prince N, et al. Expression and function of Abcg4 in the mouse blood-brain barrier: role in restricting the brain entry of amyloid-β peptide. Sci Rep. 2017;7:13393. [DOI] [PubMed] [PMC]

125.

Wang N, Lan D, Chen W, Matsuura F, Tall AR. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A. 2004;101:9774–9. [DOI] [PubMed] [PMC]

126.

Bojanic DD, Tarr PT, Gale GD, Smith DJ, Bok D, Chen B, et al. Differential expression and function of ABCG1 and ABCG4 during development and aging. J Lipid Res. 2010;51:169–81. [DOI] [PubMed] [PMC]

127.

Yang A, Alrosan AZ, Sharpe LJ, Brown AJ, Callaghan R, Gelissen IC. Regulation of ABCG4 transporter expression by sterols and LXR ligands. Biochim Biophys Acta Gen Subj. 2021;1865:129769. [DOI] [PubMed]

128.

Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M, et al. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol. 2006;26:534–40. [DOI] [PubMed]

129.

Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, et al. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem. 2004;279:41197–207. [DOI] [PubMed]

130.

Karten B, Campenot RB, Vance DE, Vance JE. Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia. J Biol Chem. 2006;281:4049–57. [DOI] [PubMed]

131.

Oram JF, Lawn RM. ABCA1: the gatekeeper for eliminating excess tissue cholesterol. J Lipid Res. 2001;42:1173–9. [DOI] [PubMed]

132.

Karasinska JM, Rinninger F, Lütjohann D, Ruddle P, Franciosi S, Kruit JK, et al. Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function. J Neurosci. 2009;29:3579–89. [DOI] [PubMed] [PMC]

133.

Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004;279:40987–93. [DOI] [PubMed]

134.

Davis W Jr. The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism. Biochim Biophys Acta. 2014; 1841:168–79. [DOI] [PubMed] [PMC]

135.

De Roeck A, Van Broeckhoven C, Sleegers K. The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics. Acta Neuropathol. 2019;138:201–20. [DOI] [PubMed] [PMC]

136.

Lyssenko NN, Praticò D. ABCA7 and the altered lipidostasis hypothesis of Alzheimer’s disease. Alzheimers Dement. 2021;17:164–74. [DOI] [PubMed] [PMC]

137.

Dib S, Pahnke J, Gosselet F. Role of ABCA7 in human health and in Alzheimer’s disease. Int J Mol Sci. 2021;22:4603. [DOI] [PubMed] [PMC]

138.

Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat Genet. 2015;47:445–7. [DOI] [PubMed]

139.

Kim WS, Hsiao JH, Bhatia S, Glaros EN, Don AS, Tsuruoka S, et al. ABCA8 stimulates sphingomyelin production in oligodendrocytes. Biochem J. 2013;452:401–10. [DOI] [PubMed]

140.

Brampton C, Pomozi V, Chen LH, Apana A, McCurdy S, Zoll J, et al. ABCC6 deficiency promotes dyslipidemia and atherosclerosis. Sci Rep. 2021;11:3881. [DOI] [PubMed] [PMC]

141.

Kuzaj P, Kuhn J, Dabisch-Ruthe M, Faust I, Götting C, Knabbe C, et al. ABCC6-a new player in cellular cholesterol and lipoprotein metabolism? Lipids Health Dis. 2014;13:118. [DOI] [PubMed] [PMC]

142.

Cserepes J, Szentpétery Z, Seres L, Ozvegy-Laczka C, Langmann T, Schmitz G, et al. Functional expression and characterization of the human ABCG1 and ABCG4 proteins: indications for heterodimerization. Biochem Biophys Res Commun. 2004;320:860–7. [DOI] [PubMed]

143.

Tarr PT, Edwards PA. ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res. 2008;49:169–82. [DOI] [PubMed]

144.

DeBose-Boyd RA, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond. Trends Biochem Sci. 2018;43:358–68. [DOI] [PubMed] [PMC]

145.

Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, et al. Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet. 2001;28:241–9. [DOI] [PubMed]

146.

Shimano H, Shimomura I, Hammer RE, Herz J, Goldstein JL, Brown MS, et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest. 1997;100:2115–24. [DOI] [PubMed] [PMC]

147.

Engelking LJ, Evers BM, Richardson JA, Goldstein JL, Brown MS, Liang G. Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin. J Clin Invest. 2006;116:2356–65. [DOI] [PubMed] [PMC]

148.

Suzuki R, Ferris HA, Chee MJ, Maratos-Flier E, Kahn CR. Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function. PLoS Biol. 2013;11:e1001532. [DOI] [PubMed] [PMC]

149.

Camargo N, Brouwers JF, Loos M, Gutmann DH, Smit AB, Verheijen MHG. High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism. FASEB J. 2012;26:4302–15. [DOI] [PubMed]

150.

Engelking LJ, Liang G, Hammer RE, Takaishi K, Kuriyama H, Evers BM, et al. Schoenheimer effect explained—feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J Clin Invest. 2005;115:2489–98. [DOI] [PubMed] [PMC]

151.

Hwang S, Nguyen AD, Jo Y, Engelking LJ, Brugarolas J, DeBose-Boyd RA. Hypoxia-inducible factor 1α activates insulin-induced gene 2 (Insig-2) transcription for degradation of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the liver. J Biol Chem. 2017;292:9382–93. [DOI] [PubMed] [PMC]

152.

Plantier L, Besnard V, Xu Y, Ikegami M, Wert SE, Hunt AN, et al. Activation of sterol-response element-binding proteins (SREBP) in alveolar type II cells enhances lipogenesis causing pulmonary lipotoxicity. J Biol Chem. 2012;287:10099–114. [DOI] [PubMed] [PMC]

153.

Bilotta MT, Petillo S, Santoni A, Cippitelli M. Liver X receptors: regulators of cholesterol metabolism, inflammation, autoimmunity, and cancer. Front Immunol. 2020;11:584303. [DOI] [PubMed] [PMC]

154.

Zhang L, Reue K, Fong LG, Young SG, Tontonoz P. Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. Arterioscler Thromb Vasc Biol. 2012;32:2541–6. [DOI] [PubMed] [PMC]

155.

Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA. Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci U S A. 2002;99:13878–83. [DOI] [PubMed] [PMC]

156.

Widenmaier SB, Snyder NA, Nguyen TB, Arduini A, Lee GY, Arruda AP, et al. NRF1 is an ER membrane sensor that is central to cholesterol homeostasis. Cell. 2017;171:1094–109.e15. [DOI] [PubMed]

157.

Lee CS, Lee C, Hu T, Nguyen JM, Zhang J, Martin MV, et al. Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration. Proc Natl Acad Sci U S A. 2011;108:8408–13. [DOI] [PubMed] [PMC]

158.

Rahimi-Balaei M, Bergen H, Kong J, Marzban H. Neuronal migration during development of the cerebellum. Front Cell Neurosci. 2018;12:484. [DOI] [PubMed] [PMC]

159.

Fan X, Kim HJ, Bouton D, Warner M, Gustafsson JA. Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons. Proc Natl Acad Sci U S A. 2008;105:13445–50. [DOI] [PubMed] [PMC]

160.

Do HT, Bruelle C, Tselykh T, Jalonen P, Korhonen L, Lindholm D. Reciprocal regulation of very low density lipoprotein receptors (VLDLRs) in neurons by brain-derived neurotrophic factor (BDNF) and Reelin: involvement of the E3 ligase Mylip/Idol. J Biol Chem. 2013;288:29613–20. [DOI] [PubMed] [PMC]

161.

Hirota Y, Kubo K, Katayama K, Honda T, Fujino T, Yamamoto TT, et al. Reelin receptors ApoER2 and VLDLR are expressed in distinct spatiotemporal patterns in developing mouse cerebral cortex. J Comp Neurol. 2015;523:463–78. [DOI] [PubMed]

162.

Meffre D, Shackleford G, Hichor M, Gorgievski V, Tzavara ET, Trousson A, et al. Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum. Proc Natl Acad Sci U S A. 2015;112:7587–92. [DOI] [PubMed] [PMC]

163.

Sakashita N, Miyazaki A, Takeya M, Horiuchi S, Chang CC, Chang TY, et al. Localization of human acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues. Am J Pathol. 2000;156:227–36. [DOI] [PubMed] [PMC]

164.

Chang TY, Chang CCY, Bryleva E, Rogers MA, Murphy SR. Neuronal cholesterol esterification by ACAT1 in Alzheimer’s disease. IUBMB Life. 2010;62:261–7. [DOI] [PubMed]

165.

Ralhan I, Chang CL, Lippincott-Schwartz J, Ioannou MS. Lipid droplets in the nervous system. J Cell Biol. 2021;220:e202102136. [DOI] [PubMed]

166.

Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. J Biol Chem. 1987;262:14352–60. [DOI] [PubMed]

167.

Mahley RW. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler Thromb Vasc Biol. 2016;36:1305–15. [DOI] [PubMed] [PMC]

168.

Do TM, Ouellet M, Calon F, Chimini G, Chacun H, Farinotti R, et al. Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood-brain barrier. Mol Cell Biochem. 2011;357:397–404. [DOI] [PubMed]

169.

Pifferi F, Laurent B, Plourde M. Lipid transport and metabolism at the blood-brain interface: implications in health and disease. Front Physiol. 2021;12:645646. [DOI] [PubMed] [PMC]

170.

Saeed AA, Genové G, Li T, Lütjohann D, Olin M, Mast N, et al. Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain. J Biol Chem. 2014;289:23712–22. [DOI] [PubMed] [PMC]

171.

Björkhem I, Lütjohann D, Breuer O, Sakinis A, Wennmalm A. Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro. J Biol Chem. 1997;272:30178–84. [DOI] [PubMed]

172.

Xie C, Lund EG, Turley SD, Russell DW, Dietschy JM. Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J Lipid Res. 2003;44:1780–9. [DOI] [PubMed]

173.

Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A. 1999;96:7238–43. [DOI] [PubMed] [PMC]

174.

Ramirez DMO, Andersson S, Russell DW. Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol. 2008;507:1676–93. [DOI] [PubMed] [PMC]

175.

Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, et al. On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett. 2001;314:45–8. [DOI] [PubMed]

176.

Cartagena CM, Ahmed F, Burns MP, Pajoohesh-Ganji A, Pak DT, Faden AI, et al. Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J Neurotrauma. 2008;25:1087–98. [DOI] [PubMed] [PMC]

177.

Smiljanic K, Lavrnja I, Mladenovic Djordjevic A, Ruzdijic S, Stojiljkovic M, Pekovic S, et al. Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner. Histochem Cell Biol. 2010;134:159–69. [DOI] [PubMed]

178.

Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CLG. Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer’s disease. J Neurochem. 2010;113:978–89. [DOI] [PubMed] [PMC]

179.

Lütjohann D, Breuer O, Ahlborg G, Nennesmo I, Sidén A, Diczfalusy U, et al. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A. 1996;93:9799–804. [DOI] [PubMed] [PMC]

180.

Ohtsuki S, Ito S, Matsuda A, Hori S, Abe T, Terasaki T. Brain-to-blood elimination of 24S-hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood-brain barrier. J Neurochem. 2007;103:1430–8. [DOI] [PubMed]

181.

Björkhem I, Lütjohann D, Diczfalusy U, Ståhle L, Ahlborg G, Wahren J. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res. 1998;39:1594–600. [DOI] [PubMed]

182.

Bretillon L, Lütjohann D, Ståhle L, Widhe T, Bindl L, Eggertsen G, et al. Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J Lipid Res. 2000;41:840–5. [DOI] [PubMed]

183.

Kim WS, Chan SL, Hill AF, Guillemin GJ, Garner B. Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons. J Alzheimers Dis. 2009;16:121–31. [DOI] [PubMed]

184.

Moutinho M, Nunes MJ, Gomes AQ, Gama MJ, Cedazo-Minguez A, Rodrigues CMP, et al. Cholesterol 24S-hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cells. Mol Neurobiol. 2015;51:1489–503. [DOI] [PubMed]

185.

Noguchi N, Saito Y, Urano Y. Diverse functions of 24(S)-hydroxycholesterol in the brain. Biochem Biophys Res Commun. 2014;446:692–6. [DOI] [PubMed]

186.

Brown AJ, Sharpe LJ, Rogers MJ. Oxysterols: from physiological tuners to pharmacological opportunities. Br J Pharmacol. 2021;178:3089–103. [DOI] [PubMed]

187.

Qi X, Liu H, Thompson B, McDonald J, Zhang C, Li X. Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi. Nature. 2019;571:279–83. [DOI] [PubMed] [PMC]

188.

Zhornitsky S, McKay KA, Metz LM, Teunissen CE, Rangachari M. Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes. Mult Scler Relat Disord. 2016;5:53–65. [DOI] [PubMed]

189.

Han M, Wang S, Yang N, Wang X, Zhao W, Saed HS, et al. Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma. EMBO Mol Med. 2020;12:e10924. [DOI] [PubMed] [PMC]

190.

Wang Y, Muneton S, Sjövall J, Jovanovic JN, Griffiths WJ. The effect of 24S-hydroxycholesterol on cholesterol homeostasis in neurons: quantitative changes to the cortical neuron proteome. J Proteome Res. 2008;7:1606–14. [DOI] [PubMed] [PMC]

191.

Gamba P, Giannelli S, Staurenghi E, Testa G, Sottero B, Biasi F, et al. The controversial role of 24-S-hydroxycholesterol in Alzheimer’s disease. Antioxidants (Basel). 2021;10:740. [DOI] [PubMed] [PMC]

192.

Sodero AO. 24S-hydroxycholesterol: cellular effects and variations in brain diseases. J Neurochem. 2021;157:899–918. [DOI] [PubMed]

193.

Yamanaka K, Saito Y, Yamamori T, Urano Y, Noguchi N. 24(S)-hydroxycholesterol induces neuronal cell death through necroptosis, a form of programmed necrosis. J Biol Chem. 2011;286:24666–73. [DOI] [PubMed] [PMC]

194.

Zarrouk A, Hammami M, Moreau T, Lizard G. Accumulation of 24S-hydroxycholesterol in neuronal SK-N-BE cells treated with hexacosanoic acid (C26:0): argument in favor of 24S-hydroxycholesterol as a potential biomarker of neurolipotoxicity. Rev Neurol (Paris). 2015;171:125–9. [DOI] [PubMed]

195.

Björkhem I, Leoni V, Svenningsson P. On the fluxes of side-chain oxidized oxysterols across blood-brain and blood-CSF barriers and origin of these steroids in CSF (review). J Steroid Biochem Mol Biol. 2019;188:86–9. [DOI] [PubMed]

196.

Heverin M, Meaney S, Lütjohann D, Diczfalusy U, Wahren J, Björkhem I. Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain. J Lipid Res. 2005;46:1047–52. [DOI] [PubMed]

197.

Zhang DD, Yu HL, Ma WW, Liu QR, Han J, Wang H, et al. 27-Hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain. Neuroscience. 2015;300:163–73. [DOI] [PubMed]

198.

Spencer TA, Gayen AK, Phirwa S, Nelson JA, Taylor FR, Kandutsch AA, et al. 24(S),25-Epoxycholesterol. Evidence consistent with a role in the regulation of hepatic cholesterogenesis. J Biol Chem. 1985;260:13391–4. [DOI] [PubMed]

199.

Goyal S, Xiao Y, Porter NA, Xu L, Guengerich FP. Oxidation of 7-dehydrocholesterol and desmosterol by human cytochrome P450 46A1. J Lipid Res. 2014;55:1933–43. [DOI] [PubMed] [PMC]

200.

Wong J, Quinn CM, Guillemin G, Brown AJ. Primary human astrocytes produce 24(S),25-epoxycholesterol with implications for brain cholesterol homeostasis. J Neurochem. 2007;103:1764–73. [DOI] [PubMed]

201.

Meljon A, Theofilopoulos S, Shackleton CHL, Watson GL, Javitt NB, Knölker HJ, et al. Analysis of bioactive oxysterols in newborn mouse brain by LC/MS. J Lipid Res. 2012;53:2469–83. [DOI] [PubMed] [PMC]

202.

Hubler Z, Friedrich RM, Sax JL, Allimuthu D, Gao F, Rivera-León AM, et al. Modulation of lanosterol synthase drives 24,25-epoxysterol synthesis and oligodendrocyte formation. Cell Chem Biol. 2021;28:866–75.e5. [DOI] [PubMed]

203.

Theofilopoulos S, Abreu de Oliveira WA, Yang S, Yutuc E, Saeed A, Abdel-Khalik J, et al. 24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo. J Biol Chem. 2019;294:4169–76. [DOI] [PubMed] [PMC]

204.

Roeper J. Dissecting the diversity of midbrain dopamine neurons. Trends Neurosci. 2013;36:336–42. [DOI] [PubMed]

205.

Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21:225–45. [DOI] [PubMed]

206.

Jin U, Park SJ, Park SM. Cholesterol metabolism in the brain and its association with Parkinson’s disease. Exp Neurobiol. 2019;28:554–67. [DOI] [PubMed] [PMC]

207.

Petrov AM, Kasimov MR, Zefirov AL. Brain cholesterol metabolism and its defects: linkage to neurodegenerative diseases and synaptic dysfunction. Acta Naturae. 2016;8:58–73. [DOI] [PubMed] [PMC]