The impact of defective cholesterol metabolism on sex-specific hepatocarcinogenesis in hepatocyte specific deletion of Cyp51 in mice
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PROVIDER: PRJNA525370 | ENA |
REPOSITORIES: ENA
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Project description:The potential role of defective cholesterol metabolism in HCC development and exposition the Cyp51 gene as a promising marker with tumor suppressor potential in sex-dimorphic chronic liver pathogenesis in mice. Hepatocyte-specific Cyp51 knock-out (KO) and wild type (WT) mice on a mixed background (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated at the age of 24 months. From each of KO mice, two samples (a tumor and a surrounding tissue) were considered.
2020-12-01 | GSE127772 | GEO
Project description:Cholesterol is one of the key molecules in mammals and the most striking examples of its deficiency are the inborn errors of cholesterol biosynthesis that manifest in severe whole body phenotypes. Liver, the principal site of cholesterol homeostasis, has rarely been investigated in these defects. We thus focused on the hepatocyte-specific deletion of lanosterol 14α-demethylase (CYP51) catalyzing the rate-limiting step in the post-squalene part of cholesterol synthesis. Liver-specific Cyp51 KO (LKO or K) and littermate control (LWT or W) mice (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated in the context of different nutritional availability of fat and cholesterol (standard laboratory diet without cholesterol (LFnC or L), high-fat diet without cholesterol (HFnC or H) and high-fat diet with cholesterol (HFC or C) due to the known sexual dimorphism in hepatic gene expression, where lipid metabolic pathways are among the most biased. 3 condition experimental design: 3 diets (LFnC or L, HFnC or H, HFC or C), 2 genotypes (LWT or W, LKO or K), 2 sexes (F, M), 3 biological replicates per condition, 36 mice altogether
2015-05-28 | E-GEOD-58271 | biostudies-arrayexpress
Project description:Unperturbed cholesterol homeostasis is important for normal development and sexual maturation in mice. Cyp51 is the rate limiting step in the post-lanosteorl part of cholesterol biosynthesis. Unlike the full body knockout, hepatocyte specific Cyp51 knockout mice survive throughout adulthood, however their livers are severly affected. Several of the hepatocyte specific Cyp51 knockout mice develop severe liver injury or die prior to reaching adulthood (from 4-10 weeks of age; designated as runts). We aim to uncover the timing and the mechanistic background governing the liver damage and sex differences. Hepatocyte-specific Cyp51 knockout and wild type mice on a mixed background (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated at the pre pubertal (3 weeks), late pubertal (6 weeks) and adult (19 weeks) stage of development. This age span allows us to also observe the impact of sexual maturation on the disease development, as the liver is one of the most sexually dimorphic non-reproductive organs. Runt mice were evaluated to differentiate them from the other KO mice with milder conditions.
2017-02-23 | GSE78892 | GEO
Project description:Cholesterol is one of the key molecules in mammals and the most striking examples of its deficiency are the inborn errors of cholesterol biosynthesis that manifest in severe whole body phenotypes. Liver, the principal site of cholesterol homeostasis, has rarely been investigated in these defects. We thus focused on the hepatocyte-specific deletion of lanosterol 14α-demethylase (CYP51) catalyzing the rate-limiting step in the post-squalene part of cholesterol synthesis. Liver-specific Cyp51 KO (LKO or K) and littermate control (LWT or W) mice (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated in the context of different nutritional availability of fat and cholesterol (standard laboratory diet without cholesterol (LFnC or L), high-fat diet without cholesterol (HFnC or H) and high-fat diet with cholesterol (HFC or C) due to the known sexual dimorphism in hepatic gene expression, where lipid metabolic pathways are among the most biased.
2015-05-28 | GSE58271 | GEO
Project description:Impaired cholesterol efflux pathways is a hallmark of lung adenocarcinoma. We used single cell RNA sequencing (scRNA-seq) to analyze the impact of defective cholesterol efflux on cell diversity in lung tumor
2023-06-01 | GSE226597 | GEO
Project description:Mice with MUTYH-null allele (Mutyh+/-, Mutyh-/-) were fed a high-fat/high-cholesterol (HFHC) diet or HFHC + high iron diet. The incidence of liver tumors and histological features of the liver were compared. We used microarray to examine the gene expression patterns associated with hepatocarcinogenesis in our model.
2020-08-31 | GSE157142 | GEO
Project description:Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC) (Picard et al., 2020). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORgt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51 by ketoconazole, a clinically approved drug, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel immune-modulation mechanism of oncometabolites and an invention strategy for the difficult-to-treat MSS CRC.
2023-11-26 | GSE248570 | GEO
Project description:Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC) (Picard et al., 2020). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORgt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51 by ketoconazole, a clinically approved drug, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel immune-modulation mechanism of oncometabolites and an invention strategy for the difficult-to-treat MSS CRC.
2023-12-02 | GSE249124 | GEO
Project description:HepG2 cell line CRISPR-Cas9 generated Knock-out in 4 cholesterol synthesis gene: CYP51, DHCR24, SC5D and HSD17B7 Excess of cholesterol associates with a variety of diseases so its synthesis must be under tight homeostatic control. The early part of cholesterol synthesis with rate-limiting HMGCR and SQLE steps is proceeded by the sterol part where numerous non-polar sterols with poorly defined biological functions are produced. To illuminate their role we developed knockouts (KO) for the consecutive enzymes that metabolize sterols towards cholesterol CYP51A1, DHCR24, SC5D resulted in the accumulation of specific set of sterols in each KO cell. Despite that, we targeted three steps of the cholesterol synthesis housekeeping pathway, the overlap of de-regulated genes was only 9%, suggesting that each set of sterols modulated the hepatic cell transcriptome uniquely. Lanosterol and 24,25-dihydrolanosterol, but not other non-polar sterols, provoked higher cell proliferation, cell cycle changes, and upregulation of metabolic pathways and transcription factors (TFs) associated with cancer progression and immune response like NFKB, SMAD, ESR1 and highly elevated LEF1 a protein from WNT signalling. In contrast, lathosterol and desmosterol caused slower proliferation and apoptosis promotion, through TFs like HNF1A and E2F. We were able to show how sterols from early part of synthesis can promote cell proliferation as sterols from end of synthesis suppress proliferation. These findings challenge the current dogma that sterols produced during cholesterol synthesis have similar biological functions
2024-08-08 | GSE221582 | GEO
Project description:ATP binding cassette transporter A1 (ABCA1) regulates cellular cholesterol efflux. We characterized the gene expression changes following hepatocyte specific ABCA1 deletion in mice. We report that genes and pathways related to lipogenesis were downregulated in mice with hepatocyte specific ABCA1 deletion compared to floxed controls.
2017-06-06 | GSE96093 | GEO