Cathepsin D regulates lipid metabolism in murine steatohepatitis

Tom Houben, Yvonne Oligschlaeger, Tim Hendrikx, Albert V. Bitorina, Sofie M. A. Walenbergh, Patrick J. van Gorp, Marion J. J. Gijbels, Silvia Friedrichs, Jogchum Plat, Frank G. Schaap, Dieter Luetjohann, Marten H. Hofker, Ronit Shiri-Sverdlov*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

29 Citations (Web of Science)

Abstract

Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism. Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.

Original languageEnglish
Article number3494
Number of pages10
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 14 Jun 2017

Keywords

  • BOWEL-DISEASE MACROPHAGES
  • NONALCOHOLIC STEATOHEPATITIS
  • DEFICIENT MICE
  • INFLAMMATION
  • APOPTOSIS
  • ATHEROSCLEROSIS
  • CHOLESTEROL
  • CELLS
  • LIVER
  • NAFLD

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