Neutral sphingomyelinase-2 and cardiometabolic diseases

Sardar Sindhu, Yat Hei Leung, Hossein Arefanian, S. R.Murthy Madiraju, Fahd Al-Mulla, Rasheed Ahmad, Marc Prentki

Research output: Contribution to journalArticlepeer-review

Abstract

Sphingolipids, in particular ceramides, play vital role in pathophysiological processes linked to metabolic syndrome, with implications in the development of insulin resistance, pancreatic ß-cell dysfunction, type 2 diabetes, atherosclerosis, inflammation, nonalcoholic steatohepatitis, and cancer. Ceramides are produced by the hydrolysis of sphingomyelin, catalyzed by different sphingomyelinases, including neutral sphingomyelinase 2 (nSMase2), whose dysregulation appears to underlie many of the inflammation-related pathologies. In this review, we discuss the current knowledge on the biochemistry of nSMase2 and ceramide production and its regulation by inflammatory cytokines, with particular reference to cardiometabolic diseases. nSMase2 contribution to pathogenic processes appears to involve cyclical feed-forward interaction with proinflammatory cytokines, such as TNF-α and IL-1ß, which activate nSMase2 and the production of ceramides, that in turn triggers the synthesis and release of inflammatory cytokines. We elaborate these pathogenic interactions at the molecular level and discuss the potential therapeutic benefits of inhibiting nSMase2 against inflammation-driven cardiometabolic diseases.

Original languageEnglish
JournalObesity Reviews
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • cardiometabolic diseases
  • ceramide
  • nSMase2
  • sphingolipid

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