Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Hepatic metabolic reprogramming during short-term caloric restriction is driven by enhanced glucocorticoid rhythms.

ABSTRACT: Caloric restriction (CR) improves metabolic health. To define how the hepatic glucocorticoid receptor (GR) supports CR-driven metabolic adaptation, we profiled its liver interactome by chromatin immunoprecipitation-mass spectrometry (ChIP-MS). Mouse livers were collected at ZT12 (glucocorticoid peak) under ad libitum or CR feeding. GR immunoprecipitates were compared to IgG controls to identify GR-associated proteins. The dataset reveals diet-dependent GR protein complexes, including transcriptional factors and metabolic coregulators, and serves as a resource for factors linking hormonal and nutritional signals to CR-induced hepatic reprogramming.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Michael Wierer

LAB HEAD: Nina Henriette Uhlenhaut

PROVIDER: PXD070287 | Pride | 2025-11-04

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	checksum.txt	Txt
	experimental_design.txt	Txt
	mqpar.xml	Xml
	raw.zip	Other
	txt.zip	Other

Items per page:

1 - 5 of 5

Similar Datasets

Beyond Myosin Heavy Chains in Human Skeletal Muscle Heterogeneity

Project description:Skeletal muscle is an inherently heterogenous tissue comprised primarily of myofibers, which are historically classified into three distinct fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X), delineated by the expression of myosin heavy chain isoforms (MYHs). However, whether discrete fiber types exist or whether fiber heterogeneity reflects a continuum remains unclear. Furthermore, whether MYHs are the main classifiers of skeletal muscle fibers has not been examined in an unbiased manner. Through the development and application of novel transcriptomic and proteomic workflows, applied to 1050 and 1038 single muscle fibers from human vastus lateralis, respectively, we show that MYHs are not the principal drivers of skeletal muscle fiber heterogeneity. Instead, ribosomal heterogeneity drives the majority of variance between skeletal muscle fibers in a continual fashion, independent of slow/fast fiber type. Furthermore, whilst slow and fast fiber clusters can be identified, described by their contractile and metabolic profiles, our data challenge the concept that type 2X are phenotypically distinct from other fast fibers at an omics level. Moreover, MYH-based classifications do not adequately describe the phenotype of skeletal muscle fibers in one of the most common genetic muscle diseases, nemaline myopathy. Our data question the currently accepted model of multiple distinct fiber types based on the expression of MYHs in humans and identifies ribosomal heterogeneity as a major driver of skeletal muscle fiber heterogeneity, opening a new field of research within skeletal muscle physiology.

2025-02-27 | PXD046863 | Pride

ChIP-MS for GR in liver from wild type and E47 mutant mice

Project description:Glucocorticoids (GCs) are widely prescribed effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a ligand-gated transcription factor. The transcriptional activation of metabolic genes by GR is thought to underlie these undesired adverse effects. Using mouse genetics, ChIP-Seq, RNA-Seq and ChIP-MS, we found that the bHLH transcription factor E47 is required for the regulation of hepatic glucose and lipid metabolism by GR in vivo, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient binding of GR to chromatin and for the adequate recruitment of coregulators such as Mediator. Taken together, our results illustrate how GR and E47 regulate hepatic metabolism, and how inhibition of E47 might provide an entry point for novel GC therapies with reduced side effect profiles. These ChIP-MS data sets show IPs for GR in both wildtype and E47 mutant mouse livers treated with the synthetic glucocorticoid Dexamethasone.

2018-11-22 | PXD010157 | Pride

Crosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells

Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.

2023-10-24 | PXD043635 | Pride

Profiling CTBP2’s genome-wide interactome in murine macrophages during LPS-induced inflammation – oligomerization-dependent interactions

Project description:To identify oligomerization dependent interactors of C-terminal binding protein 2 (CTBP2), we stably expressed CTBP2 wild type or a monomeric mutant (CTBP2 mono: CTBP2 C140Y, N144R, R147E, L156W) in Ctbp1-/-, Ctbp2-/- J774.1 cells and profiled their genome-wide interactome in LPS conditions after 3 h of stimulation. Differential profiling of CTBP2’s wild type and monomeric interactome shows oligomer-specific interactions with multiple repressors including KDM1A and the NuRD complex. Conversely, monomers retain the ability to interact with AP-1 and RNA polymerase II.

2025-06-08 | PXD063883 | Pride

Profiling CTBP2’s genome-wide interactome in murine macrophages in resting state and during LPS-induced inflammation

Project description:We profiled the genome-wide interactome of the co-repressor C-terminal binding protein 2 (CTBP2) in primary murine macrophages (BMDM) in vehicle and LPS conditions after 3 h of stimulation. We find that CTBP2 interacts with the transcription factors NF-κB and AP-1 and forms a corepressor complex that involves KDM1A, the NuRD complex and other co-repressors.

2025-06-08 | PXD063850 | Pride

Ehmt2’s transcriptional coactivation restricts glucocorticoid-induced insulin resistance in a study with male mice

Project description:Glucocorticoids play a key role in metabolic adaptation during stress, such as fasting and starvation. Excess and/or chronic glucocorticoid exposure, however, causes metabolic disorders that include insulin resistance dyslipidemia and hepatic steatosis. Glucocorticoid receptor (GR) is known to regulate a wide variety of primary target genes. However, the specificity of this regulation due to interactions with various transcriptional coactivators such as Ehmt2 remains to be further investigated. Here, we aim to identify Ehmt2 coactivation function-dependent GR primary target genes that may play a role in promoting insulin sensitivity

2023-04-07 | GSE179180 | GEO

Culturing of primary mouse hepatocytes is associated with major changes to the proteome and transcriptome

Project description:Primary hepatocytes are a commonly used in vitro model for studying liver metabolism, but prolonged culturing results in dedifferentiation. Here we characterized the transcriptome and proteome of whole liver and primary hepatocytes as either freshly isolated cells or after 24 hours of 2D-culturing. We found that after 24 hours of 2D-culturing, hepatocytes showed differential expression of over 10,000 genes and 3,000 proteins compared to freshly isolated cells. This was accompanied by a reduced transcriptional heterogeneity and a loss of zonal markers. Cultures contained ~10% non-hepatocytes, including stellate- and dedifferentiated endothelial cells. Culturing also increased abundance of proteins associated with oxidative stress and inflammation, and changed mitochondrial, extracellular, and ribosomal protein abundance. The data generated are available in the shiny-app “Hepamorphosis”. Our finding show that primary mouse hepatocytes undergo significant changes in culture, limiting theirutility for studying physiological and molecular mechanisms related to the liver.

2025-09-25 | PXD068742 | Pride

ChIP-MS of GR and in mouse liver

Project description:The Glucocorticoid Receptor (GR) is a potent metabolic regulator and a major drug target. While GR was shown to play various important roles in circadian biology, its rhythmic genomic actions have never been studied. Here we mapped GR’s genome-wide chromatin occupancy in mouse livers throughout the day/night cycle. We show how GR partitions metabolic processes during fasting (cellular maintenance, gluconeogenesis) and feeding (lipid and amino acid metabolism) by time-dependent binding and target gene regulation. Highlighting the dominant role GR plays in synchronizing circadian pathways, we find that the majority of oscillating genes harbor GR binding sites and depend on GR for amplitude stability . Surprisingly, this rhythmic pattern is altered by exposure to high fat diet in a ligand-independent manner. We show how the remodeling of oscillatory gene expression and GR binding result from a concomitant increase with Stat5 co-occupancy in obese mice, and that loss of GR reduces circulating glucose and triglycerides differentially during feeding and fasting. Altogether, our findings highlight GR’s fundamental role in the rhythmic orchestration of hepatic metabolism.

2019-10-24 | PXD014030 | Pride

From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL-D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver without significantly affecting liver injury. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. The results suggest that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver, and KC depletion further aggravates hepatic CE levels and dyslipidemia, a finding also supported by our proteomics analysis.

2024-12-01 | PXD056343 | Pride

NAD Depletion in Skeletal Muscle does not Compromise Muscle Function or Accelerate Aging

Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, the extent to which cellular NAD concentration can be decreased without deleterious repercussions is unclear. We generated a mouse model where nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance was associated with preserved tissue integrity and functionality, as demonstrated by its unchanged morphology, contractility, and exercise tolerance. This lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings indicate that NAD depletion does not contribute to age related declines in skeletal muscle function.

2025-04-23 | PXD061221 | Pride