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bioRxiv · 10.1101/2023.02.22.529551

Mass Spectrometry Reveals that Oxysterols are Secreted from Non-Alcoholic Fatty Liver Disease Induced Organoids

Komurcu, K. S.·Wilhelmsen, I.·Thorne, J. L.·Krauss, S.·Wilson, S. R.·Aizenshtadt, A.·Roberg-Larsen, H.
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Abstract

Oxysterols are potential biomarkers for liver metabolism that are altered under disease conditions such as non-alcoholic fatty liver disease (NAFLD). We here apply sterolomics to organoids used for disease modeling of NAFLD. Using liquid chromatography-mass spectrometry with on-line sample clean-up and enrichment, we establish that liver organoids produce and secrete oxysterols. We find elevated levels of 26-hydroxycholesterol, an LXR agonist and the first oxysterol in the acidic bile acid synthesis, in medium from steatotic liver organoids compared to untreated organoids. Other upregulated sterols in medium from steatotic liver organoids are dihydroxycholesterols, such as 7,26-dihydroxycholesterol, and 7,25-dihydroxycholesterol. Through 26-hydroxycholesterol exposure to human stem cell-derived hepatic stellate cells, we observe a trend of expressional downregulation of the pro-inflammatory cytokine CCL2, suggesting a protective role of 26-hydroxycholesterol during early-phased NAFLD disease development. Our findings support the possibility of oxysterols serving as NAFLD indicators, demonstrating the usefulness of combining organoids and mass spectrometry for disease modeling and biomarker studies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/529551v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@9de7fdorg.highwire.dtl.DTLVardef@e9b328org.highwire.dtl.DTLVardef@f14101org.highwire.dtl.DTLVardef@e2e9c3_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Komurcu, K. S., Wilhelmsen, I., Thorne, J. L., Krauss, S., Wilson, S. R., Aizenshtadt, A., Roberg-Larsen, H.. 2023-02-22. Mass Spectrometry Reveals that Oxysterols are Secreted from Non-Alcoholic Fatty Liver Disease Induced Organoids. https://doi.org/10.1101/2023.02.22.529551

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