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Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression [RNA-Seq]

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE205846 | GEO | 2023/08/18

REPOSITORIES: GEO

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Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression

Project description:Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRa and PPARa, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRa and PPARa for the treatment of NASH.

2023-08-18 | GSE205845 | GEO

Transcriptional regulation of insulin action and sensitivity via a GSK3β-FBXW7-ERRα axis

Project description:Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response for which transcriptional dysregulation is a major contributor. Genetic or pharmacological inhibition of the nuclear receptor ERRα preserves insulin sensitivity during diet-induced obesity. However, how ERRα integrates insulin signaling at the molecular level with whole body metabolism remains unknown. Herein, we reveal that insulin-mediated gene expression requires the nuclear stabilization of ERRα through a GSK3β/FBXW7 axis. Liver-specific deletion of GSK3β or FBXW7 or mice harboring mutations of ERRα phosphosites (ERRα3SA) co-targeted by GSK3β/FBXW7 result in accumulated ERRα proteins that no longer respond to insulin. ERRα3SA mice display reprogrammed liver and muscle transcriptomes, resulting in insulin resistance and compromised metabolic homeostasis, effects largely reversed by pharmacological inhibition of ERRα. These findings uncovered a previously unrecognised ERRα-dependent insulin regulatory pathway that could be targeted to improve insulin resistance and associated metabolic diseases.

2022-03-16 | GSE182000 | GEO

FBXW7

Project description:FBXW7

| PRJNA783287 | ENA

FBXW7

Project description:Purpose: FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance. Methods: This study was performed in 2 groups of DLD1 cells with duplicate samples per group. Both control (Wild Type, WT) and experimental (FBXW7 -/-, KO) were exposed to Tigecycline (10µM). DMSO was used as a control for the treatment. After 24h, the RNA was extracted and the transcriptome was profiled with RNA-Sequencing (RNA-seq) analysis. Results: our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.

2022-06-09 | GSE189499 | GEO

The nuclear receptors ERRα and PPARα co-ordinately control starvation-induced gene expression in hepatocytes.

Project description:Peroxisome-proliferator activated receptor α (PPARα) activation reprograms liver gene expression to support fatty acid oxidation during fasting. How PPARα engages in transcriptional programs coping with catabolic fasting responses is insufficiently understood. By applying a protein-protein interaction methodology that also captures transient interactions, we revealed the orphan nuclear receptor estrogen-related receptor α (ERRα) as a novel interaction partner of liganded PPARα and found that this interaction is enhanced following cellular nutrient starvation. Among target genes affected by PPARα-ERRα transcriptional crosstalk in fasted murine livers, multiple components of the electron transport chain were identified. Using pharmacological tools to study hepatic gene subsets under dual PPARα and ERRα control and moving from short-term to prolonged nutrient deprivation, we found that ERRα can switch from being a PPARα target gene suppressor to a marked PPARα target gene activator. Mechanistically, ERRα may control PPARα transcriptional activity via binding onto PPARα’s coactivator interaction site and via facilitating cofactor relays. In sum, a variety of crosstalk mechanisms between PPARα and ERRα seems to co-ordinately drive essential gene regulatory changes in the starving hepatocyte.

2024-04-01 | GSE200658 | GEO

Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas

Project description:We used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that tumors from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. p53+/â and p53+/âFbxw7+/â mice were generated by crossing p53-/- mice with Fbxw7+/- mice. At 5 weeks of age, mice were exposed whole-body to a single dose of 4 Gy X-ray irradiation. Mice were divided randomly into two groups and treated with rapamycin or placebo. RNA was isolated from thymic lymphomas.

2015-10-31 | E-GEOD-71975 | biostudies-arrayexpress

Effect of FBXW7 loss and concomitant FBXW7-KMT2D loss on mRNA levels

Project description:We assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. This experiment assesses the role of the FBXW7-KMT2D axis in regulating gene expression in OPM-1 cells.

2020-04-07 | GSE148131 | GEO

Targeting mitochondrial translation overcomes multidrug resistance in FBXW7-deficient cells

Project description:FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.

2022-06-08 | PXD029981 | Pride

Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas

2015-10-31 | GSE71975 | GEO

Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression

Project description:Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression

| PRJNA847943 | ENA

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