Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death
| Autor: | Christer S. Ejsing, Sandra F Gallego, Anthony H. Futerman, Richard R. Sprenger, Ole N. Jensen, Nanna Albæk, Steffen Schmidt, Marie W. Lindholm, Charlotte Øverup, Yael Pewzner-Jung, Sergey Kovalchuk, Iris D. Zelnik |
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| Rok vydání: | 2022 |
| Předmět: |
Oligonucleotides
Antisense/genetics Research & Experimental Medicine Proteomics DISEASE PCSK9 Plasma chemistry.chemical_compound 0302 clinical medicine cardiovascular disease Drug Discovery Medicine Genetics & Heredity chemistry.chemical_classification 0303 health sciences CHOLESTEROL Ceramide synthase 2 3. Good health Medicine Research & Experimental Cardiovascular Diseases Molecular Medicine ceramide synthase 2 Oxidoreductases Life Sciences & Biomedicine Ceramide government.form_of_government INHIBITION liver Ceramides ANTISENSE OLIGONUCLEOTIDES DELIVERY 03 medical and health sciences proteomics Oxidoreductases/antagonists & inhibitors Lipidomics Cardiovascular Diseases/genetics Genetics Mus musculus Humans Gene silencing Gene Silencing Molecular Biology 030304 developmental biology Pharmacology Antisense therapy Science & Technology sphingolipids business.industry ceramide biomarkers antisense therapy Oligonucleotides Antisense Sphingolipid REDUCTION MICE Enzyme Biotechnology & Applied Microbiology chemistry Hepatocytes Commentary Cancer research government RNA lipidomics LIPIDOME business Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Mol Ther Schmidt, S, Gallego, S F, Zelnik, I D, Kovalchuk, S, Albæk, N, Sprenger, R R, Øverup, C, Pewzner-Jung, Y, Futerman, A H, Lindholm, M W, Jensen, O N & Ejsing, C S 2022, ' Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death ', Molecular Therapy, vol. 30, no. 4, pp. 1661-1674 . https://doi.org/10.1016/j.ymthe.2021.08.021 |
| ISSN: | 1525-0016 |
| Popis: | 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. ispartof: MOLECULAR THERAPY vol:30 issue:4 pages:1661-1674 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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