Where Does the Heme Go? Unraveling Heme and Porphyrin Metabolism in Healthy and Oncogenic Human Livers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1117416 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, critical for detoxification and drug metabolism. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably protoporphyrin IX. Intriguingly, our recent research uncovers a disrupted heme biosynthesis process termed 'Porphyrin Overdrive' in cancers, fostering the accumulation of heme intermediates, potentially bolstering tumor survival. Here, we investigate heme and porphyrin metabolism in both healthy and oncogenic human livers, utilizing primary human liver transcriptomics and single-cell RNA sequencing (scRNAseq). Our investigations unveil robust gene expression patterns in heme biosynthesis in healthy livers, supporting electron transport chain (ETC) and cytochrome P450 function, devoid of intermediate accumulation. Conversely, liver cancers exhibit impaired heme biosynthesis and massive downregulation of cytochrome P450 expression. Notably, despite diminished drug metabolism, heme supply to the ETC remains largely unaltered or even elevated with cancer progression, suggesting a metabolic priority shift. Liver cancers selectively accumulate intermediates, absent in normal tissues, implicating their role in disease advancement as inferred by expression. Furthermore, our findings establish a link between diminished drug metabolism, augmented ETC function, porphyrin accumulation, and inferior overall survival in aggressive cancers, indicating potential targets for clinical therapy development.
2024-09-13 | GSE268462 | GEO
Project description:The increased heme biosynthesis long observed in leukemia was previously of unknown significance. Heme, synthesized from porphyrin precursors, plays a central role in oxygen metabolism and mitochondrial function, yet little is known about its role in leukemogenesis. Here we show increased expression of heme biosynthetic genes, including UROD, only in pediatric AML with high MYCN expression. Both high UROD and MYCN expression predict poor overall survival and unfavorable outcomes in adult AML. Murine leukemic progenitors derived from hematopoietic progenitor cells (HPCs) overexpressing a MYCN cDNA (MYCN-HPC) require heme/porphyrin biosynthesis, accompanied by increased oxygen consumption, to fully engage in self-renewal and oncogenic transformation. Blocking heme biosynthesis reduced mitochondrial oxygen consumption and markedly suppressed self-renewal. Leukemic progenitors rely on balanced production of heme and heme intermediates, the porphyrins. Porphyrin homeostasis is required because absence of the porphyrin exporter, ABCG2, increased death of leukemic progenitors in vitro and prolonged the survival of mice transplanted with Abcg2-KO MYCN HPCs. Pediatric AML patients with elevated MYCN mRNA display strong activation of TP53 target genes. Abcg2-KO MYCN HPCs were rescued from porphyrin toxicity by p53 loss. This vulnerability was exploited to show that treatment with a porphyrin precursor, coupled with the absence of ABCG2, blocked MYCN-driven leukemogenesis in vivo thereby demonstrating, that porphyrin homeostasis is a pathway crucial to MYCN leukemogenesis. We used microarrays to compare the global transcription profiles of hematopoietic progenitor cells from wild-type and Abcg2-ko mice that after transduction with vector-alone or vector containing MYCN gene.
2020-01-10 | GSE100437 | GEO
Project description:The risk for colon cancer is associated with nutrition, especially high fat and low calcium diets high in red meat. Red meat contains the iron porphyrin pigment heme, which induces cytotoxicity of the colon contents and epithelial hyperproliferation. Using a mouse model, we showed that heme caused damage to the colonic surface epithelium and induced compensatory hyperproliferation. Expression levels of heme- and stress-related genes show that heme affects surface cells and not directly crypt cells. Therefore, injured surface cells should signal to crypt TA cells to induce compensatory hyperproliferation. Surface-specific downregulated inhibitors of proliferation were Wnt inhibitory factor 1, Indian Hedgehog, Bone morphogenic protein 2 and possibly Interleukin-15. Heme also upregulated Amphiregulin, Epiregulin and Cyclooxygenase-2 mRNA in the surface cells, however, their protein/metabolite levels were not increased as heme induced surface-specific translation repression by increasing 4E-BP1. Therefore, we conclude that heme induced colonic hyperproliferation and hyperplasia by repressing feedback inhibition of proliferation.
2011-10-02 | GSE27848 | GEO
Project description:The risk for colon cancer is associated with nutrition, especially with diets high in red meat. Red meat contains the iron porphyrin pigment heme, which induces cytotoxicity of the colon contents and epithelial hyperproliferation. Using a mouse model, we showed that heme caused damage to the colonic surface epithelium and induced compensatory hyperproliferation. Expression levels of heme- and stress-related genes show that heme affects surface cells and not directly crypt cells. Therefore, injured surface cells should signal to crypt TA cells to induce compensatory hyperproliferation. Surface-specific downregulated inhibitors of proliferation were Wnt inhibitory factor 1, Indian Hedgehog, Bone morphogenic protein 2 and possibly Interleukin-15. Heme also upregulated Amphiregulin, Epiregulin and Cyclooxygenase-2 mRNA in the surface cells, however, their protein/metabolite levels were not increased as heme induced surface-specific translation repression by increasing 4E-BP1. Therefore, we conclude that heme induced colonic hyperproliferation and hyperplasia by repressing feedback inhibition of proliferation.
2011-10-02 | GSE27847 | GEO
Project description:Haemophilus influenzae frequently causes human disease, and humans are it’s sole niche. This bacterium has an absolute requirement for both a porphyrin and an iron source for aerobic growth, and exogenous heme can satisfy both requirements. Heme and iron can be acquired by H. influenzae from free or human protein-bound sources. The ability to selectively regulate the acquisition of heme and iron from physiological sources is a major virulence determinant for this microorganism. We utilized whole genome arrays to identify the full set of H. influenzae Rd KW20 iron and heme regulated genes. Condition specific RNA was derived from cells starved for both heme and iron and cells from the same culture 20 mins after the addition of exogenous iron and heme. The results identified 162 genes with a change in transcription ≥ 1.5 fold. Eighty genes in 42 operons were preferentially expressed under iron/ heme starvation; 82 genes in 50 operons were preferentially expressed under iron/heme replete conditions. In each case, all genes contained within the operon were co-regulated. The former group included genes encoding proteins known to have a role in iron and heme uptake as well as several hypothetical ORFs. Enzymes involved in the gluconeogenesis pathway and glycogen biosynthesis were also upregulated. The genes showing increased transcription immediately after the addition of iron and heme primarily encode proteins involved with aerobic respiration and protein biosynthesis, consistent with a relaxation of starvation. Genomic transcriptional profiling provides a more complete understanding of the effects of iron and heme availability. Keywords: Transcription analyses
2006-07-28 | GSE5061 | GEO
Project description:The risk for colon cancer is associated with nutrition, especially high fat and low calcium diets high in red meat. Red meat contains the iron porphyrin pigment heme, which induces cytotoxicity of the colon contents and epithelial hyperproliferation. Using a mouse model, we showed that heme caused damage to the colonic surface epithelium and induced compensatory hyperproliferation. Expression levels of heme- and stress-related genes show that heme affects surface cells and not directly crypt cells. Therefore, injured surface cells should signal to crypt TA cells to induce compensatory hyperproliferation. Surface-specific downregulated inhibitors of proliferation were Wnt inhibitory factor 1, Indian Hedgehog, Bone morphogenic protein 2 and possibly Interleukin-15. Heme also upregulated Amphiregulin, Epiregulin and Cyclooxygenase-2 mRNA in the surface cells, however, their protein/metabolite levels were not increased as heme induced surface-specific translation repression by increasing 4E-BP1. Therefore, we conclude that heme induced colonic hyperproliferation and hyperplasia by repressing feedback inhibition of proliferation. C57BL/6 mice received a Westernized high fat and low calcium diet with or without heme (the polyporphyrin pigment of red meat). Mice received control or heme diet for 14 days. After 14 days, mice were sacrificed and colons were taken out. RNA was isolated from colon scrapings and subjected to gene expression profiling (n=7 control mice and n=9 heme-fed mice).
2011-10-01 | E-GEOD-27848 | biostudies-arrayexpress
Project description:The risk for colon cancer is associated with nutrition, especially with diets high in red meat. Red meat contains the iron porphyrin pigment heme, which induces cytotoxicity of the colon contents and epithelial hyperproliferation. Using a mouse model, we showed that heme caused damage to the colonic surface epithelium and induced compensatory hyperproliferation. Expression levels of heme- and stress-related genes show that heme affects surface cells and not directly crypt cells. Therefore, injured surface cells should signal to crypt TA cells to induce compensatory hyperproliferation. Surface-specific downregulated inhibitors of proliferation were Wnt inhibitory factor 1, Indian Hedgehog, Bone morphogenic protein 2 and possibly Interleukin-15. Heme also upregulated Amphiregulin, Epiregulin and Cyclooxygenase-2 mRNA in the surface cells, however, their protein/metabolite levels were not increased as heme induced surface-specific translation repression by increasing 4E-BP1. Therefore, we conclude that heme induced colonic hyperproliferation and hyperplasia by repressing feedback inhibition of proliferation. C57BL/6 mice received a Westernized diet with or without heme (the polyporphyrin pigment of red meat). Mice received control or heme diet for 14 days. After 14 days, mice were sacrificed and colons were taken out. Swiss rolls were made from the middle 2 cm of the colon. These rolls were used for LCM, and surface cells and crypts cells were separately isolated. RNA was isolated from surface and crypt cells and subjected to gene expression profiling (n=4 control mice and n=3 heme-fed mice).
2011-10-01 | E-GEOD-27847 | biostudies-arrayexpress
Project description:Control of intracellular heme levels by extracellular scavenger proteins and intracellular heme oxygenases are essential functions during disease states with enhanced extracellular heme release. During severe hemolysis or rhabdomyolysis uncontrolled heme exposure can cause acute kidney injury and endothelial damage. The cytotoxic activity of heme has been primarily attributed to its pro-oxidative potential. However, the mechanisms of heme toxicity have never been systematically explored. Besides its redox reactivity, heme could also adversely alter cellular functions through its broad binding affinity to multiple non-hemoproteins. Such interactions may impair protein functions and support heme toxicity. In this study we mapped the gene expression profile of Hb triggered acute kidney injury in old blood transfused guinea pigs by serial analysis of gene expression (SAGE). Additionally, the toxic heme response of mouse embryo fibroblasts was systematically characterized on the gene and protein expression levels by gene array experiments and quantitative mass-spectrometry of stable isotope labeled cells. In all these studies, in addition to oxidative stress signals, the most significant signals were reproducibly found for biologic networks related to altered protein degradation, which ultimately triggers the response to unfolded proteins and apoptosis. These screening data could be mechanistically explained by heme-proteasome interactions and a proteasome inhibitor activity of heme. Proteasome inhibition drastically reduced the threshold of cellular toxicity during heme exposure. We therefore propose a novel model of heme toxicity whereby proteasome inhibition by the porphyrin fuels a vicious cycle of oxidative protein modification, accumulation of damaged proteins, cell damage and apoptosis.
2016-08-21 | GSE50146 | GEO
Project description:Control of intracellular heme levels by extracellular scavenger proteins and intracellular heme oxygenases are essential functions during disease states with enhanced extracellular heme release. During severe hemolysis or rhabdomyolysis uncontrolled heme exposure can cause acute kidney injury and endothelial damage. The cytotoxic activity of heme has been primarily attributed to its pro-oxidative potential. However, the mechanisms of heme toxicity have never been systematically explored. Besides its redox reactivity, heme could also adversely alter cellular functions through its broad binding affinity to multiple non-hemoproteins. Such interactions may impair protein functions and support heme toxicity. In this study we mapped the gene expression profile of Hb triggered acute kidney injury in old blood transfused guinea pigs by serial analysis of gene expression (SAGE). Additionally, the toxic heme response of mouse embryo fibroblasts was systematically characterized on the gene and protein expression levels by gene array experiments and quantitative mass-spectrometry of stable isotope labeled cells. In all these studies, in addition to oxidative stress signals, the most significant signals were reproducibly found for biologic networks related to altered protein degradation, which ultimately triggers the response to unfolded proteins and apoptosis. These screening data could be mechanistically explained by heme-proteasome interactions and a proteasome inhibitor activity of heme. Proteasome inhibition drastically reduced the threshold of cellular toxicity during heme exposure. We therefore propose a novel model of heme toxicity whereby proteasome inhibition by the porphyrin fuels a vicious cycle of oxidative protein modification, accumulation of damaged proteins, cell damage and apoptosis.
2016-08-21 | GSE50145 | GEO
Project description:Control of intracellular heme levels by extracellular scavenger proteins and intracellular heme oxygenases are essential functions during disease states with enhanced extracellular heme release. During severe hemolysis or rhabdomyolysis uncontrolled heme exposure can cause acute kidney injury and endothelial damage. The cytotoxic activity of heme has been primarily attributed to its pro-oxidative potential. However, the mechanisms of heme toxicity have never been systematically explored. Besides its redox reactivity, heme could also adversely alter cellular functions through its broad binding affinity to multiple non-hemoproteins. Such interactions may impair protein functions and support heme toxicity. In this study we mapped the gene expression profile of Hb triggered acute kidney injury in old blood transfused guinea pigs by serial analysis of gene expression (SAGE). Additionally, the toxic heme response of mouse embryo fibroblasts was systematically characterized on the gene and protein expression levels by gene array experiments and quantitative mass-spectrometry of stable isotope labeled cells. In all these studies, in addition to oxidative stress signals, the most significant signals were reproducibly found for biologic networks related to altered protein degradation, which ultimately triggers the response to unfolded proteins and apoptosis. These screening data could be mechanistically explained by heme-proteasome interactions and a proteasome inhibitor activity of heme. Proteasome inhibition drastically reduced the threshold of cellular toxicity during heme exposure. We therefore propose a novel model of heme toxicity whereby proteasome inhibition by the porphyrin fuels a vicious cycle of oxidative protein modification, accumulation of damaged proteins, cell damage and apoptosis. A two color common reference design was chosen with 2-4 independent biological replicates of each condition. Each experimental sample (Cy5 labeled) was hybridized against a non-treated reference sample (Cy3 labeled). To compensate for dye bias control arrays with competitively hybridized Cy3- and Cy5-labeled non-treated reference samples were used. The latter allowed for a very robust statistical analysis with pair-wise comparison of treatment array replicates versus the corresponding control array replicates.
2016-08-21 | E-GEOD-50145 | biostudies-arrayexpress