Knockouts of CYP51A1, DHCR24, or SC5D from cholesterol synthesis reveal pathways modulated by sterol intermediates

Skubic, Cene (author), Trček, Hana (author), Nassib, Petra (author), Kreft, Tinkara (author), Walakira, Andrew (author), Pohar, Katka (author), Petek, Sara (author), Režen, Tadeja (author), Ihan, Alojz (author), Rozman, Damjana (author)

Sterols from cholesterol synthesis are crucial for cholesterol production, but also have individual roles difficult to assess in vivo due to essentiality of cholesterol. We developed HepG2 cell models with knockouts (KOs) for three enzymes of cholesterol synthesis, each accumulating specific sterols. Surprisingly, KOs of CYP51, DHCR24, and SC5D shared only 9% of differentially expressed genes. The most striking was the phenotype of CYP51 KO with highly elevated lanosterol and 24,25-dihydrolanosterol, significant increase in G2+M phase and enhanced cancer and cell cycle pathways. Comparisons with mouse liver Cyp51 KO data suggest 24,25-dihydrolanosterol activates similar cell proliferation pathways, possibly via elevated LEF1 and WNT/NFKB signaling. In contrast, SC5D and DHCR24 KO cells with elevated lathosterol or desmosterol proliferated slowly, with downregulated E2F, mitosis, and enriched HNF1A. These findings demonstrate that increase of lanosterol and 24,25-dihydrolanosterol, but not other sterols, promotes cell proliferation in hepatocytes.

• Language: English
• Keywords: cholesterol synthesis, sterol intermediates, CYP51A1, DHCR24, SC5D, cellular physiology, cell biology
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 18 str.
• Numbering: Vol. 27, iss. 9, art. 110651
• PID: 20.500.12556/RUL-165279
• UDC: 61:578
• ISSN on article: 2589-0042
• DOI: 10.1016/j.isci.2024.110651
• COBISS.SI-ID: 206739203
• Publication date in RUL: 29.11.2024

Record is a part of a journal

• Title: iScience
• Publisher: Elsevier
• ISSN: 2589-0042
• COBISS.SI-ID: 24098568

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: sinteza holesterola, intermediati sterola, CYP51A1, DHCR24, SC5D