Sphingomyelin synthase–related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease

Yeun po Chiang, Zhiqiang Li, Mulin He, Quiana Jones, Meixia Pan, Xianlin Han, Xian Cheng Jiang

Research output: Contribution to journalArticlepeer-review

Abstract

Sphingomyelin synthase (SMS)–related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency–mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr KO and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency–mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose–induced fatty liver and NASH, and attenuated glucosylceramide accumulation–induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PE-PLC deficiency or PE supplementation effectively prevented membrane-bound β-catenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor β1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.

Original languageEnglish (US)
Article number105162
JournalJournal of Biological Chemistry
Volume299
Issue number9
DOIs
StatePublished - Sep 2023

Keywords

  • liver fibrosis
  • nonalcoholic fatty liver disease (NAFLD)
  • nonalcoholic steatohepatitis (NASH)
  • phosphatidylethanolamine
  • phosphatidylethanolamine phospholipase C
  • sphingomyelin synthase–related protein

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Sphingomyelin synthase–related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease'. Together they form a unique fingerprint.

Cite this