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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE205845 | 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 [RNA-Seq]

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 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.

2023-08-18 | GSE205846 | GEO

FBXW7

Project description:FBXW7

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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.

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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.

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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.

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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.

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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

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

| PRJNA847937 | ENA

Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC

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2024-06-16 | PXD043904 | Pride

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