دورية أكاديمية
Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death.
| العنوان: | Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death. |
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| المؤلفون: | Schmidt S; Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark., Gallego SF; Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark., Zelnik ID; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel., Kovalchuk S; Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark., Albæk N; Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark., Sprenger RR; Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark., Øverup C; Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark., Pewzner-Jung Y; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel., Futerman AH; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel., Lindholm MW; Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark., Jensen ON; Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark., Ejsing CS; Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. Electronic address: cse@bmb.sdu.dk. |
| المصدر: | Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Apr 06; Vol. 30 (4), pp. 1661-1674. Date of Electronic Publication: 2021 Aug 14. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2017- : Cambridge, MA : Cell Press Original Publication: San Diego, CA : Academic Press, 2000- |
| مواضيع طبية MeSH: | Cardiovascular Diseases*/genetics , Oligonucleotides, Antisense*/genetics , Oxidoreductases*/antagonists & inhibitors, Biomarkers ; Ceramides ; Gene Silencing ; Hepatocytes ; Humans ; Plasma |
| مستخلص: | 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. Competing Interests: 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. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Comment in: Mol Ther. 2022 Apr 6;30(4):1359-1360. (PMID: 35279234) |
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| فهرسة مساهمة: | Keywords: Mus musculus; antisense therapy; cardiovascular disease; ceramide biomarkers; ceramide synthase 2; hepatocytes; lipidomics; liver; proteomics; sphingolipids |
| المشرفين على المادة: | 0 (Biomarkers) 0 (Ceramides) 0 (Oligonucleotides, Antisense) EC 1.- (Oxidoreductases) EC 1.3.1.- (dihydroceramide desaturase) |
| تواريخ الأحداث: | Date Created: 20210817 Date Completed: 20220411 Latest Revision: 20230407 |
| رمز التحديث: | 20230407 |
| مُعرف محوري في PubMed: | PMC9077316 |
| DOI: | 10.1016/j.ymthe.2021.08.021 |
| PMID: | 34400330 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1525-0024 |
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| DOI: | 10.1016/j.ymthe.2021.08.021 |