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Cited by 7Sphingolipid Metabolism and SignalingCholesterol and Lipid MetabolismCancer, Lipids, and Metabolism

Cholesterol-induced robust Ca oscillation in astrocytes required for survival and lipid droplet formation in high-cholesterol condition.

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Adachi, Chihiro, Otsuka, Shio, Inoue, Takafumi·2022·iScience
DOI 10.1016/j.isci.2022.105138PMC PMC9523397
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Abstract

Cholesterol, one of the major cell membrane components, stabilizes membrane fluidity and regulates signal transduction. Beside its canonical roles, cholesterol has been reported to directly activate signaling pathways such as hedgehog (Hh). We recently found that astrocytes, one of the glial cells, respond to Hh pathway stimulation by Ca signaling. These notions led us to test if extracellularly applied cholesterol triggers Ca signaling in astrocytes. Here, we found that cholesterol application induces robust Ca oscillation only in astrocytes with different properties from the Hh-induced Ca response. The Ca oscillation has a long delay which corresponds to the onset of cholesterol accumulation in the plasma membrane. Blockade of the Ca oscillation resulted in enhancement of astrocytic cell death and disturbance of lipid droplet formation, implying a possibility that the cholesterol-induced Ca oscillation plays important roles in astrocytic survival and cholesterol handling under pathological conditions of cholesterol load such as demyelination.

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  • Cholesterol levels did not differ between human or mouse FMRP-deficient and control astrocyte conditioned medium, suggesting that astrocytes maintained extracellular cholesterol homeostasis to avoid cholesterol toxicity.

    “Here, cholesterol levels did not differ between human or mouse FMRP-deficient and control astrocyte conditioned medium, suggesting that astrocytes maintained extracellular cholesterol homeostasis to avoid cholesterol toxicity (Adachi et al., 2022; Talvio et al., 2023).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Adachi et al., 2022

    The Results section on astrocyte viability reports increased cell death under high extracellular cholesterol, and the Discussion says cholesterol-induced Ca oscillations help astrocytes survive that load. The paper does not show that astrocytes maintain extracellular cholesterol homeostasis; it also does not compare cholesterol levels in conditioned medium from FMRP-deficient and control astrocytes. Page numbers were not provided in our copy. (LLM, conf=0.84)

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Research works printed but not linked: 62

  1. Adachi C. Kakinuma N. Jo S.H. Ishii T. Arai Y. Arai S. Kitaguchi T. Takeda S. Inoue T. Sonic hedgehog enhances calcium oscillations in hippocampal astrocytes J. Biol. Chem. 294 2019 16034 16048 10.1074/jbc.RA119.007883 31506300 PMC6827318 · DOI
  2. Andersson L. Boström P. Ericson J. Rutberg M. Magnusson B. Marchesan D. Ruiz M. Asp L. Huang P. Frohman M.A. PLD1 and ERK2 regulate cytosolic lipid droplet formation J. Cell Sci. 119 2006 2246 2257 10.1242/jcs.02941 16723731 · DOI
  3. Avila-Muñoz E. Arias C. Cholesterol-induced astrocyte activation is associated with increased amyloid precursor protein expression and processing Glia 63 2015 2010 2022 10.1002/glia.22874 26096015 · DOI
  4. Axmann M. Strobl W.M. Plochberger B. Stangl H. Cholesterol transfer at the plasma membrane Atherosclerosis 290 2019 111 117 10.1016/j.atherosclerosis.2019.09.022 31605876 · DOI
  5. Baek S.-J. Park A. Ahn Y.-J. Choo J. Baseline correction using asymmetrically reweighted penalized least squares smoothing Analyst 140 2015 250 257 10.1039/C4AN01061B 25382860 · DOI
  6. Bagur R. Hajnóczky G. Intracellular Ca2+sensing: its role in calcium homeostasis and signaling Mol. Cell 66 2017 780 788 10.1016/j.molcel.2017.05.028 28622523 PMC5657234 · DOI · Paper page
  7. Brahmachari S. Fung Y.K. Pahan K. Induction of glial fibrillary acidic protein expression in astrocytes by Nitric Oxide J. Neurosci. 26 2006 4930 4939 10.1523/JNEUROSCI.5480-05.2006 16672668 PMC1963412 · DOI · Paper page
  8. Brennan D. Chen X. Cheng L. Mahoney M. Riobo N.A. Noncanonical hedgehog signaling Vitam. Horm. 88 2012 55 72 10.1016/B978-0-12-394622-5.00003-1 22391299 PMC3513281 · DOI
  9. Cannarozzo C. Fred S.M. Girych M. Biojone C. Enkavi G. Róg T. Vattulainen I. Casarotto P.C. Castrén E. Cholesterol-recognition motifs in the transmembrane domain of the tyrosine kinase receptor family: the case of TRKB Eur. J. Neurosci. 53 2021 3311 3322 10.1111/ejn.15218 33825223 · DOI
  10. Chen Y.L. Wang L.M. Chen Y. Gao J.Y. Marshall C. Cai Z.Y. Hu G. Xiao M. Changes in astrocyte functional markers and β-amyloid metabolism-related proteins in the early stages of hypercholesterolemia Neuroscience 316 2016 178 191 10.1016/j.neuroscience.2015.12.039 26724580 · DOI
  11. Chun Y.S. Oh H.G. Park M.K. Kim T.-W. Chung S. Increasing membrane cholesterol level increases the Amyloidogenic peptide by enhancing the expression of phospholipase C J. Neurodegener. Dis. 2013 2013 407903 10.1155/2013/407903 26316988 PMC4437359 · DOI
  12. Crabtree G.R. Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT Cell 96 1999 611 614 10.1016/S0092-8674(00)80571-1 10089876 · DOI
  13. DeKosky S.T. Statin therapy in the treatment of Alzheimer disease: what is the rationale? Am. J. Med. 118 2005 48 53 10.1016/j.amjmed.2005.09.006 16356808 · DOI
  14. Deshpande I. Liang J. Hedeen D. Roberts K.J. Zhang Y. Ha B. Latorraca N.R. Faust B. Dror R.O. Beachy P.A. Smoothened stimulation by membrane sterols drives Hedgehog pathway activity Nature 571 2019 284 288 10.1038/s41586-019-1355-4 31263273 PMC6709672 · DOI
  15. Dolmetsch R.E. Lewis R.S. Goodnow C.C. Healy J.I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration Nature 386 1997 855 858 10.1038/386855a0 9126747 · DOI
  16. Dolmetsch R.E. Xu K. Lewis R.S. Calcium oscillations increase the efficiency and specificity of gene expression Nature 392 1998 933 936 10.1038/31960 9582075 · DOI
  17. Dorris D.M. Hauser C.A. Minnehan C.E. Meitzen J. An aerator for brain slice experiments in individual cell culture plate wells J. Neurosci. Methods 238 2014 1 10 10.1016/j.jneumeth.2014.09.017 25256645 · DOI
  18. Eng L.F. Ghirnikar R.S. GFAP and astrogliosis Brain Pathol 4 1994 229 237 10.1111/j.1750-3639.1994.tb00838.x 7952264 · DOI · Paper page
  19. Fong B.S. Angel A. Transfer of free and esterified cholesterol from low-density lipoproteins and high-density lipoproteins to human adipocytes Biochim. Biophys. Acta 1004 1989 53 60 10.1016/0005-2760(89)90212-9 2742874 · DOI
  20. Fowler S.D. Greenspan P. Application of Nile red, a fluorescent hydrophobic probe, for the detection of neutral lipid deposits in tissue sections: comparison with oil red O J. Histochem. Cytochem. 33 1985 833 836 10.1177/33.8.4020099 4020099 · DOI · Paper page
  21. Funakoshi T. Aki T. Tajiri M. Unuma K. Uemura K. Necroptosis-like neuronal cell death caused by cellular cholesterol accumulation J. Biol. Chem. 291 2016 25050 25065 10.1074/jbc.M116.727404 27756839 PMC5122773 · DOI
  22. Galland F. Seady M. Taday J. Smaili S.S. Gonçalves C.A. Leite M.C. Astrocyte culture models: molecular and function characterization of primary culture, immortalized astrocytes and C6 glioma cells Neurochem. Int. 131 2019 104538 10.1016/j.neuint.2019.104538 31430518 · DOI
  23. Gimpl G. Interaction of G protein coupled receptors and cholesterol Chem. Phys. Lipids 199 2016 61 73 10.1016/j.chemphyslip.2016.04.006 27108066 · DOI
  24. Huang P. Nedelcu D. Watanabe M. Jao C. Kim Y. Liu J. Salic A. Cellular cholesterol directly activates smoothened in hedgehog signaling Cell 166 2016 1176 1187.e14 10.1016/j.cell.2016.08.003 27545348 PMC5035717 · DOI
  25. Huang Y.N. Lin C.I. Liao H. Liu C.Y. Chen Y.H. Chiu W.C. Lin S.H. Cholesterol overload induces apoptosis in SH-SY5Y human neuroblastoma cells through the up regulation of flotillin-2 in the lipid raft and the activation of BDNF/Trkb signaling Neuroscience 328 2016 201 209 10.1016/j.neuroscience.2016.04.043 27155148 · DOI
  26. Ihaka R. Gentleman R. R: aLanguage for data analysis and graphics J. Comput. Graph Stat. 5 1996 299 314 10.2307/1390807 · DOI
  27. Ikonen E. Cellular cholesterol trafficking and compartmentalization Nat. Rev. Mol. Cell Biol. 9 2008 125 138 10.1038/nrm2336 18216769 · DOI
  28. Inoue T. TI Workbench, an integrated software package for electrophysiology and imaging Microscopy 67 2018 129 143 10.1093/jmicro/dfy015 29554288 · DOI
  29. Jenkins D. Hedgehog signalling: emerging evidence for non-canonical pathways Cell. Signal. 21 2009 1023 1034 10.1016/j.cellsig.2009.01.033 19399989 · DOI
  30. Kanemaru K. Sekiya H. Xu M. Satoh K. Kitajima N. Yoshida K. Okubo Y. Sasaki T. Moritoh S. Hasuwa H. In vivo visualization of subtle, transient, and local activity of astrocytes using an ultrasensitive Ca2+indicator Cell Rep. 8 2014 311 318 10.1016/j.celrep.2014.05.056 24981861 · DOI
  31. Kupzig S. Walker S.A. Cullen P.J. The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade Proc. Natl. Acad. Sci. USA 102 2005 7577 7582 10.1073/pnas.0409611102 15890781 PMC1103707 · DOI
  32. Lange S.C. Bak L.K. Waagepetersen H.S. Schousboe A. Norenberg M.D. Primary cultures of astrocytes: their value in understanding astrocytes in health and disease Neurochem. Res. 37 2012 2569 2588 10.1007/s11064-012-0868-0 22926576 PMC4737437 · DOI
  33. Langness V.F. van der Kant R. Das U. Wang L. Chaves R. Dos S. Goldstein L.S.B. Cholesterol lowering drugs reduce APP processing to Aβ by inducing APP dimerization Mol. Biol. Cell 32 2020 247 259 10.1091/mbc.E20-05-0345 33296223 PMC8098827 · DOI
  34. Lingwood D. Simons K. Lipid rafts as a membrane-organizing principle Science 327 2010 46 50 10.1126/science.1174621 20044567 · DOI · Paper page
  35. Lu X. Liu J. Hou F. Liu Z. Cao X. Seo H. Gao B. Cholesterol induces pancreatic β cell apoptosis through oxidative stress pathway Cell Stress Chaperones 16 2011 539 548 10.1007/s12192-011-0265-7 21472505 PMC3156264 · DOI
  36. Luchetti G. Sircar R. Kong J.H. Nachtergaele S. Sagner A. Byrne E.F. Covey D.F. Siebold C. Rohatgi R. Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling Elife 5 2016 e20304 10.7554/eLife.20304 27705744 PMC5123864 · DOI
  37. Lütjohann D. Papassotiropoulos A. Björkhem I. Locatelli S. Bagli M. Oehring R.D. Schlegel U. Jessen F. Rao M.L. von Bergmann K. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients J. Lipid Res. 41 2000 195 198 10681402
  38. Marchesan D. Rutberg M. Andersson L. Asp L. Larsson T. Borén J. Johansson B.R. Olofsson S.-O. A phospholipase D-dependent process forms lipid droplets containing Caveolin, Adipocyte differentiation-related protein, and Vimentin in a cell-free system J. Biol. Chem. 278 2003 27293 27300 10.1074/jbc.M301430200 12730229 · DOI
  39. Murphy R.C. Johnson K.M. Cholesterol, reactive oxygen species, and the formation of biologically active mediators J. Biol. Chem. 283 2008 15521 15525 10.1074/jbc.R700049200 18285330 PMC2414298 · DOI
  40. Nagai T. Yamada S. Tominaga T. Ichikawa M. Miyawaki A. Expanded dynamic range of fluorescent indicators for Ca2+ by circularly permuted yellow fluorescent proteins Proc. Natl. Acad. Sci. USA 101 2004 10554 10559 10.1073/pnas.0400417101 15247428 PMC490022 · DOI · Paper page
  41. Newton J. Palladino E.N.D. Weigel C. Maceyka M. Gräler M.H. Senkal C.E. Enriz R.D. Marvanova P. Jampilek J. Lima S. Targeting defective sphingosine kinase 1 in Niemann-Pick type C disease with an activator mitigates cholesterol accumulation J. Biol. Chem. 295 2020 9121 9133 10.1074/jbc.RA120.012659 32385114 PMC7335787 · DOI
  42. Norman A.W. Demel R.A. de Kruyff B. van Deenen L.L.M. Studies on the biological properties of polyene antibiotics: evidence for the direct interactionoffilipin with cholesterol J. Biol. Chem. 247 1972 1918 1929 10.1016/S0021-9258(19)45558-0 5012767 · DOI
  43. Olzmann J.A. Carvalho P. Dynamics and functions of lipid droplets Nat. Rev. Mol. Cell Biol. 20 2019 137 155 10.1038/s41580-018-0085-z 30523332 PMC6746329 · DOI · Paper page
  44. Paila Y.D. Chattopadhyay A. Membrane cholesterol in the function and organization of G-protein coupled receptors Subcell. Biochem. 51 2010 439 466 10.1007/978-90-481-8622-8_16 20213554 · DOI
  45. Paul R. Borah A. Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice Sci. Rep. 7 2017 17922 10.1038/s41598-017-17911-z 29263397 PMC5738385 · DOI
  46. Refolo L.M. Pappolla M.A. Malester B. LaFrancois J. Bryant-Thomas T. Wang R. Tint G.S. Sambamurti K. Duff K. hypercholesterolemia accelerates the alzheimer’s amyloid pathology in a transgenic mouse model Neurobiol. Dis. 7 2000 321 331 10.1006/nbdi.2000.0304 10964604 · DOI
  47. Reynolds I.J. Hastings T.G. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation J. Neurosci. 15 1995 3318 3327 10.1523/JNEUROSCI.15-05-03318.1995 7751912 PMC6578215 · DOI · Paper page
  48. Richner M. Jager S.B. Siupka P. Vaegter C.B. Hydraulic Extrusion of the Spinal Cord and Isolation of Dorsal Root Ganglia in Rodents J. Vis. Exp. 55226 2017 10.3791/55226 PMC5352284 28190031 · DOI
  49. Samios V.N. Inoue T. Interleukin-1β and interleukin-6 affect electrophysiological properties of thalamic relay cells Neurosci. Res. 87 2014 16 25 10.1016/j.neures.2014.06.011 25091392 · DOI
  50. Slotte J.P. Chait A. Bierman E.L. Cholesterol accumulation in aortic smooth muscle cells exposed to low density lipoproteins. Contribution of free cholesterol transfer Arteriosclerosis 8 1988 750 758 10.1161/01.ATV.8.6.750 3196219 · DOI
  51. Tauffenberger A. Magistretti P.J. Reactive oxygen species: beyond their reactive behavior Neurochem. Res. 46 2021 77 87 10.1007/s11064-020-03208-7 33439432 PMC7829243 · DOI
  52. Thirumangalakudi L. Prakasam A. Zhang R. Bimonte-Nelson H. Sambamurti K. Kindy M.S. Bhat N.R. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice J. Neurochem. 106 2008 475 485 10.1111/j.1471-4159.2008.05415.x 18410513 PMC3897170 · DOI
  53. Vincent L. Soille P. Watersheds in digital spaces: an efficient algorithm based on immersion simulations IEEE Trans. Pattern Anal. Mach. Intell. 13 1991 583 598 10.1109/34.87344 · DOI
  54. Wang H. Kulas J.A. Wang C. Holtzman D.M. Ferris H.A. Hansen S.B. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol Proc. Natl. Acad. Sci. USA 118 2021 10.1073/pnas.2102191118 e2102191118 PMC8379952 34385305 · DOI
  55. Wang Y. DelRosso N.V. Vaidyanathan T.V. Cahill M.K. Reitman M.E. Pittolo S. Mi X. Yu G. Poskanzer K.E. Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology Nat. Neurosci. 22 2019 1936 1944 10.1038/s41593-019-0492-2 31570865 PMC6858541 · DOI · Paper page
  56. Wüstner D. Mondal M. Huang A. Maxfield F.R. Different transport routes for high density lipoprotein and its associated free sterol in polarized hepatic cells J. Lipid Res. 45 2004 427 437 10.1194/jlr.M300440-JLR200 14679167 · DOI
  57. Xu M. Liu K. Swaroop M. Porter F.D. Sidhu R. Firnkes S. Finkes S. Ory D.S. Marugan J.J. Xiao J. δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders J. Biol. Chem. 287 2012 39349 39360 10.1074/jbc.M112.357707 23035117 PMC3501083 · DOI
  58. Yang L. Yao H. Chen X. Cai Y. Callen S. Buch S. Role of Sigma receptor in cocaine-mediated induction of glial fibrillary acidic protein: Implications for HAND Mol. Neurobiol. 53 2016 1329 1342 10.1007/s12035-015-9094-5 25631712 PMC4519438 · DOI
  59. Yin J. Chaufour X. McLachlan C. McGuire M. White G. King N. Hambly B. Apoptosis of vascular smooth muscle cells induced by cholesterol and its oxides in vitro and in vivo Atherosclerosis 148 2000 365 374 10.1016/s0021-9150(99)00286-5 10657573 · DOI
  60. Zhang Y. Barres B.A. Astrocyte heterogeneity: an underappreciated topic in neurobiology Curr. Opin. Neurobiol. 20 2010 588 594 10.1016/j.conb.2010.06.005 20655735 · DOI
  61. Zhornitsky S. McKay K.A. Metz L.M. Teunissen C.E. Rangachari M. Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes Mult. Scler. Relat. Disord. 5 2016 53 65 10.1016/j.msard.2015.10.005 26856944 · DOI
  62. Zidovetzki R. Levitan I. Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies Biochim. Biophys. Acta 1768 2007 1311 1324 10.1016/j.bbamem.2007.03.026 17493580 PMC1948080 · DOI

Cited by

Sorted by citations

Authors
Adachi, C., Otsuka, S., & Inoue, T.
Affiliations
Waseda University (JP)
Corresponding author
Inoue, Takafumi
ORCID
Inoue, Takafumi
Venue
iScience
Publisher
Elsevier BV
Published
2022-10
Volume
25
Issue
10
Pages
105138
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2022.105138
PMC
PMC9523397
OpenAlex
W4296202015
Cited by
7
References
2
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 2
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Waseda University (2019C-715, 2020C-644, 2020C-778, 2021C-559, 2021C-733, 2021E-023)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
cholesterol, calcium oscillations, astrocytes, lipid droplet formation, astrocyte survival, cell death, Hedgehog signaling, demyelination

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