Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death.
Mus musculus
antisense therapy
cardiovascular disease
ceramide biomarkers
ceramide synthase 2
hepatocytes
lipidomics
liver
proteomics
sphingolipids
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
06 04 2022
06 04 2022
Historique:
received:
15
05
2021
revised:
26
07
2021
accepted:
08
08
2021
pubmed:
18
8
2021
medline:
12
4
2022
entrez:
17
8
2021
Statut:
ppublish
Résumé
Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders.
Identifiants
pubmed: 34400330
pii: S1525-0016(21)00415-9
doi: 10.1016/j.ymthe.2021.08.021
pmc: PMC9077316
pii:
doi:
Substances chimiques
Biomarkers
0
Ceramides
0
Oligonucleotides, Antisense
0
Oxidoreductases
EC 1.-
dihydroceramide desaturase
EC 1.3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1661-1674Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests S.S. and N.A. are, and M.W.L. and C.Ø. were, at the time of the making of this work, full-time employees of Roche Innovation Center Copenhagen. The remaining authors declare no competing interests.
Références
Cell Metab. 2018 Feb 6;27(2):276-280
pubmed: 29307517
Histochem Cell Biol. 2013 Nov;140(5):533-47
pubmed: 23591958
Prog Lipid Res. 2016 Jul;63:93-119
pubmed: 27180613
Front Endocrinol (Lausanne). 2020 Jul 29;11:483
pubmed: 32849276
PLoS One. 2017 Nov 21;12(11):e0188394
pubmed: 29161304
Br J Clin Pharmacol. 2015 Dec;80(6):1350-61
pubmed: 26261033
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):1903-7
pubmed: 21245337
J Biol Chem. 2012 Jun 15;287(25):21025-33
pubmed: 22539345
Chem Rev. 2011 Oct 12;111(10):6387-422
pubmed: 21942574
Nucleic Acids Res. 2010 Nov;38(20):7100-11
pubmed: 20615897
Sci Rep. 2017 Apr 28;7:45040
pubmed: 28452372
J Biol Chem. 2016 Apr 1;291(14):7477-87
pubmed: 26887952
Mol Ther Nucleic Acids. 2017 Mar 17;6:89-105
pubmed: 28325303
Sci Rep. 2019 Jul 17;9(1):10369
pubmed: 31316083
J Am Soc Mass Spectrom. 2015 Jan;26(1):133-48
pubmed: 25391725
Hepatology. 2013 Feb;57(2):525-32
pubmed: 22911490
Eur Heart J. 2016 Jul 01;37(25):1967-76
pubmed: 27125947
Biochem J. 2012 Feb 1;441(3):789-802
pubmed: 22248339
Nat Methods. 2018 Jul;15(7):515-518
pubmed: 29786091
Front Endocrinol (Lausanne). 2020 Sep 29;11:570628
pubmed: 33133018
J Lipid Res. 2013 Jun;54(6):1523-1530
pubmed: 23549332
Mol Ther Nucleic Acids. 2016 May 03;5:e317
pubmed: 27138177
Nucleic Acids Res. 2014 Jul;42(13):8796-807
pubmed: 24992960
Chembiochem. 2015 Apr 13;16(6):903-8
pubmed: 25786782
Mol Cell Proteomics. 2019 Feb;18(2):383-390
pubmed: 30373789
Nat Genet. 2019 Jun;51(6):957-972
pubmed: 31152163
Nat Commun. 2019 Apr 23;10(1):1847
pubmed: 31015462
Cell Rep. 2019 Jan 2;26(1):1-10.e7
pubmed: 30605666
PLoS One. 2016 Jul 21;11(7):e0159431
pubmed: 27442522
Cell Rep. 2021 Feb 2;34(5):108710
pubmed: 33535053
PLoS Med. 2017 Sep 12;14(9):e1002383
pubmed: 28898252
Nat Rev Endocrinol. 2020 Apr;16(4):224-233
pubmed: 32060415
Nat Commun. 2019 Jan 3;10(1):29
pubmed: 30604766
PLoS One. 2013 Nov 07;8(11):e79736
pubmed: 24244551
J Biol Chem. 2016 Mar 25;291(13):6989-7003
pubmed: 26853464
J Biol Chem. 2010 Apr 2;285(14):10911-23
pubmed: 20110366
Nucleic Acid Ther. 2020 Feb;30(1):4-13
pubmed: 31618108
Cell. 2019 May 30;177(6):1536-1552.e23
pubmed: 31150623
J Biol Chem. 2010 Apr 2;285(14):10902-10
pubmed: 20110363
Mol Cell. 2019 Dec 5;76(5):811-825.e14
pubmed: 31628041
J Clin Endocrinol Metab. 2014 Jan;99(1):E45-52
pubmed: 24243630
Nat Protoc. 2016 Dec;11(12):2301-2319
pubmed: 27809316
Biochim Biophys Acta. 2014 May;1841(5):671-81
pubmed: 24021978
J Biol Chem. 2018 Jun 22;293(25):9912-9921
pubmed: 29632068
Mol Ther. 2012 Feb;20(2):376-81
pubmed: 22108858
Mol Ther Nucleic Acids. 2020 Sep 4;21:242-250
pubmed: 32590173
Diabetologia. 2018 Jun;61(6):1424-1434
pubmed: 29546476
EMBO Rep. 2004 Aug;5(8):777-82
pubmed: 15289826
Diabetes. 2018 Aug;67(8):1663-1672
pubmed: 29588286
Mol Ther Nucleic Acids. 2018 Jun 1;11:441-454
pubmed: 29858079
FEBS Lett. 2007 Nov 13;581(27):5289-94
pubmed: 17977534
Nucleic Acids Res. 2010 Jan;38(1):e3
pubmed: 19854938
Cell Metab. 2014 Oct 7;20(4):678-86
pubmed: 25295788
Prog Lipid Res. 2016 Jan;61:51-62
pubmed: 26703189
Diabetologia. 2018 Dec;61(12):2570-2579
pubmed: 30159588
Mol Metab. 2019 Mar;21:36-50
pubmed: 30655217
Stat Appl Genet Mol Biol. 2004;3:Article3
pubmed: 16646809
J Biol Chem. 2012 Jan 27;287(5):3197-206
pubmed: 22144673
Elife. 2014 Oct 03;3:
pubmed: 25279700
Diabetes. 2002 Apr;51(4):1028-34
pubmed: 11916922
N Engl J Med. 2019 Jan 3;380(1):57-70
pubmed: 30601736
J Biol Chem. 2009 Nov 27;284(48):33549-60
pubmed: 19801672
J Lipid Res. 2009 Apr;50 Suppl:S9-14
pubmed: 19098281
Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2136-41
pubmed: 19174513