Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death

Steffen Schmidt, Sandra F Gallego, Iris Daphne Zelnik, Sergey Kovalchuk, Nanna Albæk, Richard R Sprenger, Charlotte Øverup, Yael Pewzner-Jung, Anthony H Futerman, Marie W Lindholm, Ole N Jensen, Christer S Ejsing

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Abstract

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.

Original languageEnglish
JournalMolecular Therapy
Volume30
Issue number4
Pages (from-to)1661-1674
ISSN1525-0016
DOIs
Publication statusPublished - 6. Apr 2022

Keywords

  • Mus musculus
  • antisense therapy
  • cardiovascular disease
  • ceramide biomarkers
  • ceramide synthase 2
  • hepatocytes
  • lipidomics
  • liver
  • proteomics
  • sphingolipids
  • Oligonucleotides, Antisense/genetics
  • Plasma
  • Cardiovascular Diseases/genetics
  • Humans
  • Gene Silencing
  • Oxidoreductases/antagonists & inhibitors
  • Hepatocytes
  • Biomarkers
  • Ceramides

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