CoChat
Sign Up
Cited by 151Multiple Sclerosis Research StudiesNeurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration Mechanisms

Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

Open access
Berghoff, Stefan A., Gerndt, Nina, Winchenbach, Jan, Stumpf, Sina K., Hosang, Leon, Odoardi, Francesca, Ruhwedel, Torben, Böhler, Carolin +7 more·2017·Nature Communications
DOI 10.1038/ncomms14241PMC PMC5286209
Open this paper in CoChat — free accountOpen PDF

Abstract

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ncomms14241

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • External cholesterol supply in diet accelerates remyelination in demyelination models with or without reduced fatty acid synthesis.

    “This is consistent with previous report that external cholesterol supply in diet accelerates the remyelination process in demyelination model with or in models with reduced fatty acid synthesis (Berghoff et al. 2017;Dimas et al. 2019).”

    From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Berghoff et al. 2017

    The Results section reports that dietary cholesterol enhanced remyelination in a lysolecithin-induced demyelination model, and the Discussion describes improved repair in the cuprizone model. These passages support the dietary-cholesterol finding, but they do not establish its effect in a model with reduced fatty acid synthesis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 62

  1. Irvine K. A. & Blakemore W. F. Remyelination protects axons from demyelination-associated axon degeneration. Brain 131, 1464– 1477 (2008). 18490361
  2. Moyon S.. Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration. J. Neurosci. 35, 4– 20 (2015). 25568099 PMC6605244
  3. Kuhlmann T.. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131, 1749– 1758 (2008). 18515322
  4. Franklin R. J. & ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839– 855 (2008). 18931697
  5. Rodgers J. M., Robinson A. P. & Miller S. D. Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis. Discov. Med. 16, 53– 63 (2013). 23911232 PMC3970909
  6. Harsan L. A.. Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging. J. Neurosci. 28, 14189– 14201 (2008). 19109501 PMC3844750
  7. Skripuletz T.. Pivotal role of choline metabolites in remyelination. Brain 138, 398– 413 (2015). 25524711
  8. de la Fuente A. G.. Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J. Cell Biol. 211, 975– 985 (2015). 26644513 PMC4674280
  9. Huang J. K.. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 14, 45– 53 (2011). 21131950 PMC4013508
  10. Vuletic S.. Cerebrospinal fluid apolipoprotein E and phospholipid transfer protein activity are reduced in multiple sclerosis; relationships with the brain MRI and CSF lipid variables. Mult. Scler. Relat. Disord. 3, 533– 541 (2014). 24955324 PMC4061752
  11. Teunissen C. E.. Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients. Neurosci. Lett. 347, 159– 162 (2003). 12875910
  12. Giubilei F.. Blood cholesterol and MRI activity in first clinical episode suggestive of multiple sclerosis. Acta Neurol. Scand. 106, 109– 112 (2002). 12100371
  13. Weinstock-Guttman B.. Lipid profiles are associated with lesion formation over 24 months in interferon-beta treated patients following the first demyelinating event. J. Neurol. Neurosurg. Psychiatry 84, 1186– 1191 (2013). 23595944
  14. Tettey P.. An adverse lipid profile is associated with disability and progression in disability, in people with MS. Mult. Scler. 20, 1737– 1744 (2014). 24829292
  15. Saher G.. High cholesterol level is essential for myelin membrane growth. Nat. Neurosci. 8, 468– 475 (2005). 15793579
  16. Saher G.. Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet. Nat. Med. 18, 1130– 1135 (2012). 22706386
  17. Raddatz B. B.. Central Nervous System Demyelination and Remyelination is Independent from Systemic Cholesterol Level in Theiler's Murine Encephalomyelitis. Brain Pathol. 26, 102– 119 (2016). 25959295 PMC8029487
  18. Suzuki K. Giant hepatic mitochondria: production in mice fed with cuprizone. Science 163, 81– 82 (1969). 5763494
  19. Abbott N. J.. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37, 13– 25 (2010). 19664713
  20. Saeed A. A.. Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain. J. Biol. Chem. 289, 23712– 23722 (2014). 24973215 PMC4156098
  21. Kondo A., Nakano T. & Suzuki K. Blood-brain barrier permeability to horseradish peroxidase in twitcher and cuprizone-intoxicated mice. Brain Res. 425, 186– 190 (1987). 3427420
  22. Boretius S.. Assessment of lesion pathology in a new animal model of MS by multiparametric MRI and DTI. Neuroimage 59, 2678– 2688 (2012). 21914485
  23. Holtta-Vuori M.. BODIPY-cholesterol: a new tool to visualize sterol trafficking in living cells and organisms. Traffic 9, 1839– 1849 (2008). 18647169
  24. Gudi V.. Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming. PLOS ONE 6, e22623 (2011). 21818353 PMC3144923
  25. Jurevics H.. Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination. J. Neurochem. 82, 126– 136 (2002). 12091473
  26. Mason J. L.. Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am. J. Pathol. 164, 1673– 1682 (2004). 15111314 PMC1615641
  27. Lürbke A.. Limited TCF7L2 expression in MS lesions. PLOS ONE 8, e72822 (2013). 23977356 PMC3748032
  28. Hammond E.. The Wnt Effector Transcription Factor 7-Like 2 Positively Regulates Oligodendrocyte Differentiation in a Manner Independent of Wnt/beta-Catenin Signaling. J. Neurosci. 35, 5007– 5022 (2015). 25810530 PMC6705374
  29. Fancy S. P.. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev. 23, 1571– 1585 (2009). 19515974 PMC2704469
  30. Liebetanz D. & Merkler D. Effects of commissural de- and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis. Exp. Neurol. 202, 217– 224 (2006). 16857191
  31. Fünfschilling U.. Critical time window of neuronal cholesterol synthesis during neurite outgrowth. J. Neurosci. 32, 7632– 7645 (2012). 22649242 PMC6703588
  32. Courtney R. & Landreth G. E. LXR regulation of brain cholesterol: from development to disease. Trends Endocrinol. Metab. 27, 404– 414 (2016). 27113081 PMC4986614
  33. Woodruff R. H., Fruttiger M., Richardson W. D. & Franklin R. J. Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol. Cell Neurosci. 25, 252– 262 (2004). 15019942
  34. Lindner M.. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9. Brain 138, 1875– 1893 (2015). 25907862 PMC7185739
  35. Wu M.. Differential modulation of the oligodendrocyte transcriptome by sonic hedgehog and bone morphogenetic protein 4 via opposing effects on histone acetylation. J Neurosci. 32, 6651– 6664 (2012). 22573687 PMC3412138
  36. Fortin D., Rom E., Sun H., Yayon A. & Bansal R. Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage. J. Neurosci. 25, 7470– 7479 (2005). 16093398 PMC6725305
  37. Jurevics H. & Morell P. Cholesterol for synthesis of myelin is made locally, not imported into brain. J. Neurochem. 64, 895– 901 (1995). 7830084
  38. Zhao C.. Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation. Nat. Commun. 7, 10883 (2016). 26955760 PMC4786870
  39. Miron V. E.. Statin therapy inhibits remyelination in the central nervous system. Am. J. Pathol. 174, 1880– 1890 (2009). 19349355 PMC2671276
  40. Youssef S.. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78– 84 (2002). 12422218
  41. Stanislaus R., Singh A. K. & Singh I. Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis. J. Neurosci. Res. 66, 155– 162 (2001). 11592110
  42. Greenwood J.. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 17, 905– 907 (2003). 12626426 PMC3831156
  43. Pihl-Jensen G., Tsakiri A. & Frederiksen J. L. Statin treatment in multiple sclerosis: a systematic review and meta-analysis. CNS Drugs 29, 277– 291 (2015). 25795002
  44. Lock C.. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500– 508 (2002). 11984595
  45. Werring D. J.. The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain 123, 1667– 1676 (2000). 10908196
  46. Morra V. B.. Interferon-beta treatment decreases cholesterol plasma levels in multiple sclerosis patients. Neurology 62, 829– 830 (2004). 15007146
  47. Zhou Y. X., Pannu R., Le T. Q. & Armstrong R. C. Fibroblast growth factor 1 (FGFR1) modulation regulates repair capacity of oligodendrocyte progenitor cells following chronic demyelination. Neurobiol. Dis. 45, 196– 205 (2012). 21854849 PMC3225566
  48. Hibbits N., Yoshino J., Le T. Q. & Armstrong R. C. Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination. ASN Neuro 4, 393– 408 (2012). 23025787 PMC3483617
  49. Olah M.. Identification of a microglia phenotype supportive of remyelination. Glia 60, 306– 321 (2012). 22072381
  50. Mohan H.. Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination. Acta Neuropathol. Commun. 2, 168 (2014). 25589163 PMC4359505
  51. Furusho M., Roulois A. J., Franklin R. J. & Bansal R. Fibroblast growth factor signaling in oligodendrocyte-lineage cells facilitates recovery of chronically demyelinated lesions but is redundant in acute lesions. Glia 63, 1714– 1728 (2015). 25913734 PMC4534313
  52. Ornitz D. M. & Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 4, 215– 266 (2015). 25772309 PMC4393358
  53. Clemente D., Ortega M. C., Arenzana F. J. & de C. F. FGF-2 and Anosmin-1 are selectively expressed in different types of multiple sclerosis lesions. J. Neurosci. 31, 14899– 14909 (2011). 22016523 PMC6623557
  54. Han M. H.. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076– 1081 (2008). 18278032
  55. Ito J., Nagayasu Y., Miura Y., Yokoyama S. & Michikawa M. Astrocytes endogenous apoE generates HDL-like lipoproteins using previously synthesized cholesterol through interaction with ABCA1. Brain Res. 1570, 1– 12 (2014). 24814386
  56. Winer S.. Obesity predisposes to Th17 bias. Eur. J. Immunol. 39, 2629– 2635 (2009). 19662632
  57. Timmermans S.. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system. J. Neuroimmune Pharmacol. 9, 209– 217 (2014). 24068577
  58. Haghikia A.. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817– 829 (2015). 26488817
  59. Stromnes I. M. & Goverman J. M. Active induction of experimental allergic encephalomyelitis. Nat. Protoc. 1, 1810– 1819 (2006). 17487163
  60. Brinkmann B. G.. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59, 581– 595 (2008). 18760695 PMC2628490
  61. Steelman A. J., Thompson J. P. & Li J. Demyelination and remyelination in anatomically distinct regions of the corpus callosum following cuprizone intoxication. Neurosci. Res. 72, 32– 42 (2012). 22015947 PMC3230728
  62. Thomson C. E.. Myelinated, synapsing cultures of murine spinal cord--validation as an in vitro model of the central nervous system. Eur. J. Neurosci. 28, 1518– 1535 (2008). 18793322 PMC2777255

Cited by

Sorted by citations

Authors
Berghoff, S. A., Gerndt, N., Winchenbach, J., Stumpf, S. K., Hosang, L., Odoardi, F., Ruhwedel, T., Böhler, C., Barrette, B., Stassart, R., Liebetanz, D., Dibaj, P., Möbius, W., Edgar, J. M., & Saher, G.
Affiliations
  • Max Planck Institute of Experimental Medicine (DE)
  • Universitätsmedizin Göttingen (DE)
  • University of Göttingen (DE)
  • Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
Corresponding author
Saher, Gesine
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-01-24
Volume
8
Issue
1
Pages
14241-14241
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms14241
PMC
PMC5286209
OpenAlex
W2581477543
Cited by
151
References
8
Citations by year
2026: 13 · 2025: 13 · 2024: 6 · 2023: 11 · 2022: 25 · 2021: 26 · 2020: 26 · 2019: 16 · 2018: 11 · 2017: 4
FWCI
12.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • GRO (submittedVersion, cc-by)
Funders
Deutsche Forschungsgemeinschaft (SA 2014/2-1)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
dietary cholesterol, remyelination, multiple sclerosis, demyelination, cuprizone, experimental autoimmune encephalomyelitis, myelination, blood-brain barrier, axonal injury, motor learning, cholesterol supplementation
MeSH terms
Animals, Axons, Brain, Cell Differentiation, Cells, Cultured, Cholesterol, Cholesterol, Dietary, Cuprizone, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Humans, Male, Mice, Inbred C57BL, Multiple Sclerosis, Myelin Proteins, Oligodendroglia, Stem Cells, Biomarkers, Dietary Supplements, Cell Proliferation, Mice, Primary Cell Culture

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review