20.500.12556/RUL-165279 Knockouts of CYP51A1, DHCR24, or SC5D from cholesterol synthesis reveal pathways modulated by sterol intermediates 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. cholesterol synthesis sterol intermediates CYP51A1 DHCR24 SC5D cellular physiology cell biology sinteza holesterola intermediati sterola CYP51A1 DHCR24 SC5D true false true Angleški jezik Slovenski jezik Članek v reviji 2024-11-29 08:34:05 2024-11-29 08:34:07 2026-01-29 07:58:31 0000-00-00 00:00:00 2024 0 0 18 str. iss. 9, art. 110651 Vol. 27 Sept. 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 61:578 2589-0042 10.1016/j.isci.2024.110651 206739203 RAZ_Skubic_Cene_2024.pdf RAZ_Skubic_Cene_2024.pdf 1 52EA352185E4DF9CF96C976457C221DC 45c397a2237cf6f5576a53c48e6d522bbe6be51cd4c55804350ebd5222588e83 12b0c209-ae25-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=196354 https://www.sciencedirect.com/science/article/pii/S2589004224018765 0 057bd17b-41ed-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211088 https://www.cell.com/iscience/fulltext/S2589-0042(24)01876-5 1 e76155dd-ae23-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=196353 Medicinska fakulteta 0 0 0