AMPK stimulation and PGC-1 alpha suppression in peroxisome deficient hepatocytes favor catabolic over anabolic carbohydrate metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE27720 | GEO | 2012/01/06
SECONDARY ACCESSION(S): PRJNA138091
REPOSITORIES: GEO
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Project description:These arrays contain data from the livers of 10 week old L-Pex5 -/- male mice 6 arrays, 3 biological replicates
2012-01-06 | E-GEOD-27720 | biostudies-arrayexpress
Project description:Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5(-/-) mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD(+)/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5(-/-) mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor ? (PPAR?) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor ? null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1? was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies.
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Project description:Peroxisome biogenesis diseases (PBDs) are characterized by global defects in peroxisomal function and can result in severe brain, liver, kidney, and bone malfunctions. PBDs are due to mutations in peroxisome biogenesis factors (PEX genes) that are responsible for peroxisome assembly and function. Increasing evidence suggests that peroxisome import functions decline during aging. However, the transcriptome profiling of peroxisome import defects and how they affect disease development are still lacking. PEX5 encodes the cytoplasmic receptors for peroxisome-targeting signal types 1. We generate knock-in human HEK293 cells mutant using CRISPR to transiently express PEX5 cysteine 11 to alanine mutant (PEX5C11A), which blocks PEX5 recycling and exerts dominant negative effect on PEX5 mediated peroxisome import. To identify conserved responses, we perform transcriptomic analysis on Drosophila oenocyte-specific Pex1, Pex12 and Pex5 knockdowns and on human cells with impaired peroxisome import (through expressing PEX5C11A and applying PEX5 siRNA respectively). PEX5C11A induction triggers vast transcriptomic changes, including decreased oxidative phosphorylation, increased MAPK signaling and HIPPO signaling. PEX5 siRNA specifically decreases spliceosome activity and increases cholesterol metabolism. Using gene set enrichment analysis (GSEA), we identify protein processing in endoplasmic reticulum pathway, specifically ER-associated protein degradation (ERAD) pathway is induced in all PEX knockdowns in Drosophila. Peroxisome dysfunction elevates eIF2α phosphorylation in both Drosophila and human cell culture independent of XBP1 activation, suggesting increased integrative stress response (ISR). Moreover, peroxisome stress decreases ribosome biogenesis genes and impairs ribosome biogenesis in flies and human cells. Specifically, peroxisome stress impairs the 5'-ETS cleavage activity during the ribosome biogenesis and dampens 40S small ribosomal export in both flies and human. Our results suggest that reduced ribosome biogenesis and elevated ISR could be conserved cellular response to peroxisome import stress.
2021-02-23 | GSE167197 | GEO
Project description:This project sought to identify the features in PEX5 required for interaction with the peroxisomal PEX2-PEX10-PEX12 ubiquitin ligase complex. Peroxisomes equilibrated with different PEX5 mutants (i.e., C11A, AH1, AH2) were purified from Xenopus egg extract, solubilized in digitonin, and PEX5-associated material was immunoprecipitated via a C-terminal FLAG tag. PEX5 without a FLAG tag was used as a negative control. PEX5-interacting peroxins were identified by LC-MS/MS at the Taplin Mass Spectrometry Facility at Harvard Medical School.
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Project description:Vibration in the form of High Frequency Acceleration (HFA) is anabolic on the craniofacial skeleton in the absence of inflammation. Orthodontic forces trigger an inflammation-dependent catabolic cascade that is crucial for tooth movement. It is unknown what effect HFA has on alveolar bone if applied during orthodontic treatment. The objectives of this study are to examine the effect of HFA on the rate of tooth movement and alveolar bone, and determine the mechanism by which HFA affects tooth movement. Adult Sprague Dawley rats were divided to control, orthodontic force alone (OTM), and different experimental groups that received the same orthodontic forces and different HFA regimens. Orthodontic tooth movement was assessed when HFA parameters, frequency, acceleration, duration of exposure, and direct or indirect application were varied. We found that HFA treatment significantly enhanced the inflammation-dependent catabolic cascade during orthodontic tooth movement. HFA treatment increased inflammatory mediators and osteoclastogenesis, and decreased alveolar bone density during orthodontic tooth movement. Each of the HFA variables produced significant changes in the rate of tooth movement and the effect was PDL-dependent. This is the first report that HFA enhances inflammation-dependent catabolic cascades in bone. The clinical implications of our study are highly significant, as HFA can be utilized to enhance the rate of orthodontic tooth movement during the catabolic phase of treatment and subsequently be utilized to enhance retention during the anabolic remodeling phase after orthodontic forces are removed.
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Project description:D-amino acids exist in living organisms as specialized components of many different machineries. Biosynthesis of D-amino acids from racemization of predominant L-enantiomers is catalyzed by a single enzyme. Here, we report the finding of a novel 2-component amino acid racemase for D-to-L inversion in D-arginine metabolism of Pseudomonas aeruginosa. From DNA microarray analysis, the putative dauBAR operon (for D-arginine utilization) of unknown functions was found to be highly induced by D-arginine. The importance of the dau operon in D-arginine metabolism was demonstrated by the findings that strains with a lesion at dauA or dauB failed to use D-arginine as sole carbon source. Two lines of evidence suggest that DauA and DauB are required for D-to-L racemization of arginine. First, growth complementation of an L-arginine auxotroph by D-arginine was abolished by a lesion at dauA or dauB. Second, D-arginine induced L-arginine-specific genes in the parental strain PAO1 but not in its dauA or dauB mutants. This hypothesis was further supported by activity measurements of the purified enzymes: DauA catalyzes oxidative deamination of D-arginine into 2-ketoarginine and ammonia, and DauB is able to use 2-ketoarginine and ammonia as substrates and convert them into L-arginine in the presence of NADPH or NADH. Thus, we propose that DauA and DauB are coupled catabolic and anabolic dehydrogenases to perform D-to-L racemization of arginine, which serves as prerequisite of D-arginine utilization through L-arginine catabolic pathways.
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Project description:AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK ? regulatory subunit and phosphorylates the AMPK ? catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the ? subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.
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Project description:BACKGROUND:Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. OBJECTIVE:This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. METHODS:Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. RESULTS:We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. CONCLUSIONS:Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.
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Project description:A large proportion of the global soil carbon pool is stored in soils of high-latitude ecosystems in which microbial processes and production of greenhouse gases proceed during the winter months. It has been suggested that microorganisms have limited ability to sequester substrates at temperatures around and below 0 °C and that a metabolic shift to dominance of catabolic processes occurs around these temperatures. However, there are contrary indications that anabolic processes can proceed, because microbial growth has been observed at far lower temperatures. Therefore, we investigated the utilization of the microbial substrate under unfrozen and frozen conditions in a boreal forest soil across a temperature range from -9 °C to +9 °C, by using gas chromatography-isotopic ratio mass spectrometry and (13)C magic-angle spinning NMR spectroscopy to determine microbial turnover and incorporation of (13)C-labeled glucose. Our results conclusively demonstrate that the soil microorganisms maintain both catabolic (CO(2) production) and anabolic (biomass synthesis) processes under frozen conditions and that no significant differences in carbon allocation from [(13)C]glucose into [(13)C]CO(2) and cell organic (13)C-compounds occurred between +9 °C and -4 °C. The only significant metabolic changes detected were increased fluidity of the cell membranes synthesized at frozen conditions and increased production of glycerol in the frozen samples. The finding that the processes in frozen soil are similar to those in unfrozen soil has important implications for our general understanding and conceptualization of soil carbon dynamics in high-latitude ecosystems.
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Project description:ObjectiveRegulation of anabolic and catabolic factors is considered essential in maintaining the homoeostasis of healthy articular cartilage. In this study we investigated the influence of RNA binding proteins (RNABPs) in this process.DesignUsing small interfering RNA (siRNA), RNABP expression was knocked down in SW1353 chondrosarcoma cells and human articular chondrocytes. Gene expression and messenger RNA (mRNA) decay of anabolic (SOX9, Aggrecan) and catabolic (matrix metalloproteinase (MMP)13) factors were analysed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). RNA-electromobility shift assays (EMSAs) were used to investigate RNABP interactions with the SOX9 mRNA 3' untranslated region (UTR). Immunohistochemical localisation of MMP13 and the RNABP human antigen R (HuR) was performed in E13.5 and E16.5 mouse embryo sections.ResultsSOX9 mRNA, mRNA half-life and protein expression were increased with siRNA targeting the RNABP tristetraprolin (TTP) in both HACs and SW1353s. TTP knockdown also stimulated aggrecan mRNA expression but did not affect its stability. RNA-EMSAs demonstrated that adenine uracil (AU)-rich elements in the SOX9 mRNA 3'UTR interacted with chondrocyte proteins with three specific elements interacting with TTP. HuR knockdown significantly increased MMP13 expression and also regulated the expression of a number of known transcriptional repressors of MMP13. HuR was ubiquitously expressed within mouse embryos yet displayed regional down-regulation within developing skeletal structures.ConclusionThis study demonstrates for the first time how RNABPs are able to affect the balance of anabolic and catabolic gene expression in human chondrocytes. The post-transcriptional mechanisms controlled by RNABPs present novel avenues of regulation and potential points of intervention for controlling the expression of SOX9 and MMP13 in chondrocytes.
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