Human Sterols are Overproduced, Stored and Excreted in Yeasts

Astrid Radkohl, Veronika Schusterbauer, Lukas Bernauer, Gerald Rechberger, Heimo Wolinski, Matthias Schittmayer, Ruth Birner-Gruenberger, Gerhard Thallinger, Erich Leitner, Melanie Baeck, Harald Pichler, Anita Emmerstorfer-Augustin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Sterols exert a profound influence on numerous cellular processes, playing a crucial role in both health and disease. However, comprehending the effects of sterol dysfunction on cellular physiology is challenging. Consequently, numerous processes affected by impaired sterol biosynthesis still elude our complete understanding. In this study, we made use of yeast strains that produce cholesterol instead of ergosterol and investigated the cellular response mechanisms on the transcriptome as well as the lipid level. The exchange of ergosterol for cholesterol caused the downregulation of phosphatidylethanolamine and phosphatidylserine and upregulation of phosphatidylinositol and phosphatidylcholine biosynthesis. Additionally, a shift towards polyunsaturated fatty acids was observed. While the sphingolipid levels dropped, the total amounts of sterols and triacylglycerol increased, which resulted in 1.7-fold enlarged lipid droplets in cholesterol-producing yeast cells. In addition to internal storage, cholesterol and its precursors were excreted into the culture supernatant, most likely by the action of ABC transporters Snq2, Pdr12 and Pdr15. Overall, our results demonstrate that, similarly to mammalian cells, the production of non-native sterols and sterol precursors causes lipotoxicity in K. phaffii, mainly due to upregulated sterol biosynthesis, and they highlight the different survival and stress response mechanisms on multiple, integrative levels.

Original languageEnglish
Article number781
Number of pages22
JournalInternational Journal of Molecular Sciences
Volume25
Issue number2
DOIs
Publication statusPublished - 8 Jan 2024

Keywords

  • cholesterol
  • ergosterol
  • Komagataella phaffii
  • lipid droplets
  • lipotoxicity
  • Pichia pastoris
  • plasma membrane
  • sphingolipids
  • yeast

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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