T3 and Glucose Increase Expression of Phosphoenolpyruvate Carboxykinase (Pck1) Leading to Increased ß-Cell Proliferation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA903166 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR22334900_1.fastq.gz | Fastqsanger.gz | |||
| SRR22334900_2.fastq.gz | Fastqsanger.gz | |||
| SRR22334902_1.fastq.gz | Fastqsanger.gz | |||
| SRR22334902_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 39 |
Similar Datasets
Project description:Thyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation
2023-11-18 | GSE218334 | GEO
Project description:Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally down-regulated protein 8, to target proteins, with yet-unknown consequences. Here we show in mice that neddylation in liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver (either pharmacologically or genetically) reduces gluconeogenic capacity and the hyperglycemic actions of counterregulatory hormones (glucagon, adrenaline and glucocorticoids). Further, people with obesity and type 2 diabetes (compared to people with obesity and normoglycemia) display elevated hepatic neddylation levels that correlate positively with fasting glucose levels. Mechanistically, we determined that fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342 and K387. PCK1 is a key control point for gluconeogenesis regulation that can be post-translationally modified by acetylation and phosphorylation, but to date no modifications are known to affect its gluconeogenic capacity. Of note, we find that mutating the three PCK1 lysines that are neddylated reduces its gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely-tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
2023-10-08 | PXD043054 | Pride
Project description:Metabolic dysregulation may serve as a pivotal driver of inflammatory bowel disease (IBD), with the crosstalk between metabolism and the immune system emerging as a critical research focus. Ulcerative colitis (UC) patients exhibit enhanced glycolysis but suppressed gluconeogenesis in the intestinal mucosa, yet the mechanistic links between these metabolic alterations and mucosal injury remain poorly defined. This study establishes phosphoenolpyruvate carboxykinase 1 (Pck1), a key rate-limiting enzyme in gluconeogenesis, as a central regulator of UC progression. We found Pck1 expression was significantly downregulated in colon tissues of UC patients and mice with DSS‑induced colitis. Utilizing an intestinal epithelial cell (IEC)-specific Pck1 knockout mouse model, we demonstrated for the first time that Pck1 deficiency exacerbates intestinal inflammation. Mechanistically, Pck1 depletion induces metabolic reprogramming that upregulates Pla2g6 expression, driving abnormal hydrolysis of phosphatidylcholine and phosphatidylethanolamine in IECs. Pharmacological inhibition of Pla2g6 ameliorated colitis in Pck1-deficient mice. These findings position Pck1 as a potential early diagnostic biomarker for UC and suggest that therapeutic targeting of the Pck1-Pla2g6 metabolic axis may yield novel strategies for UC management.
2025-05-05 | GSE295845 | GEO
Project description:The protein-tyrosine phosphatase SHP-1 (PTPN6) is an important glucose homeostasis modulator. Besides negatively regulating insulin signaling, the specific role of SHP-1 in metabolic control remains poorly understood. We show that SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene, thereby modulating basal gluconeogenesis in hepatocytes. SHP-1 interacts with RNA polymerase II-subunits and signal transducer and activator of transcription 5 (STAT5), and localizes to the nucleus, where a sub-fraction of SHP-1 associates with chromatin. While SHP-1 binds to the PCK1-promoter, its loss affects RNA polymerase II-recruitment to this and other promoters of genes enriched for glucose metabolism-related functions. SHP-1-downregulation, and similarly STAT5 pharmacological inhibition reduce PCK1-transcript levels correlating with blunted gluconeogenesis. Overall, we identified a novel molecular SHP-1-function, that of a regulator of PCK1-transcription and subsequently hepatic gluconeogenesis, through physical interaction with the transcription machinery, mediated by an Akt-independent mechanism, but independent of STAT5 tyrosine-phosphorylation status.
2023-09-08 | GSE174142 | GEO
Project description:ObjectivesThyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation.MethodsRNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human β-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR.ResultsWe found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPβ) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human β-cells. In β-cells, T3 and glucose coordinately regulate the expression of ChREBPβ and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for β-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human β-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased β-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPβ contributes to Pck1-dependent β-cell proliferation in mouse β-cells.ConclusionsWe conclude that T3 and glucose act together to regulate ChREBPβ, leading to increased expression and activity of Pck1, and ultimately increased β-cell proliferation.
| S-EPMC9731891 | biostudies-literature
Project description:Metabolic dysregulation may serve as a pivotal driver of inflammatory bowel disease (IBD), with the crosstalk between metabolism and the immune system emerging as a critical research focus. Ulcerative colitis (UC) patients exhibit enhanced glycolysis but suppressed gluconeogenesis in the intestinal mucosa, yet the mechanistic links between these metabolic alterations and mucosal injury remain poorly defined. This study establishes phosphoenolpyruvate carboxykinase 1 (Pck1), a key rate-limiting enzyme in gluconeogenesis, as a central regulator of UC progression. We found Pck1 expression was significantly downregulated in colon tissues of UC patients and mice with DSS‑induced colitis. Utilizing an intestinal epithelial cell (IEC)-specific Pck1 knockout mouse model, we demonstrated for the first time that Pck1 deficiency exacerbates intestinal inflammation. Mechanistically, Pck1 depletion induces metabolic reprogramming that upregulates Pla2g6 expression, driving abnormal hydrolysis of phosphatidylcholine and phosphatidylethanolamine in IECs. Pharmacological inhibition of Pla2g6 ameliorated colitis in Pck1-deficient mice. These findings position Pck1 as a potential early diagnostic biomarker for UC and suggest that therapeutic targeting of the Pck1-Pla2g6 metabolic axis may yield novel strategies for UC management.
2025-05-07 | GSE296485 | GEO
Project description:The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen also blunted NASH-HCC transition when applied therapeutically in two independent models of diet-induced NASH and NASH-HCC. The timing (7pm-7pm > 7am-7am), length (24h > 12h) and number (5:2 > 6:1) of fasting cycles as well as the type (WD / CDHFD) of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteome, transcriptome and metabolome analyses identified that PPARα and glucocorticoid signalling-induced phosphoenolpyruvate carboxykinase 1 (PCK1) act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis while suppressing anabolic lipogenesis. In line, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting during the active phase (7pm-7pm) of mice robustly induced glucocorticoid signalling in hepatocytes including PCK1 expression; while both active and inactive phase (7am-7am) fasting induced free fatty acid-induced PPARα signalling, highlighting the increased efficacy of fasting during the active phase. However, hepatocyte-specific glucocorticoid receptor (GR) deletion only partially abrogated the hepatic fasting response, illustrating the need for both glucocorticoid-induced PCK1 expression and free fatty acid-induced PPARα activation for mediating the benefits of fasting. In support, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis upon Western-diet feeding. Altogether, our data support that the IF 5:2 regimen could be a promising and viable intervention against NASH and subsequent liver cancer.
2024-05-29 | GSE255356 | GEO
Project description:cDNA microarray analysis was applied to primary cultures of rat hepatic cells treated with triiodothyronine (T3) at 10-9 M for 24 hrs to identify the differentially expressed genes. A limited number of genes were listed, and only 3 of them, pyridoxal kinase (Pdxk), phosphoe-nolpyruvate carboxykinase 1 (Pck1), and solute carrier family 17 member 2 (Slc17a2), were con-firmed to be up-regulated by quantitative RT-PCR.
2024-11-27 | GSE282664 | GEO
Project description:We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P.pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose ammonium (Bio-) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (∆ROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ∆ROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ∆ROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ∆ROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ∆ROP strain. To our knowledge, ROP is the first example, of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions.
2011-10-14 | GSE32948 | GEO
Project description:Elucidation of metabolic flux and switch is fundamental for understanding of CD8+ memory T (Tm) cell development. Glycogen, an intracellular carbon reservoir, has long been functionally considered as the use of energy metabolism. However, our recent study indicated that glycogen metabolism, directed by a cytosolic phosphoenolpyruvate carboxykinase (Pck1), controls the formation and maintenance of CD8+ Tm cells through regulating the redox homeostasis1. This unusual metabolic program raises the question of how Pck1 is upregulated in CD8+ Tm cells. Here, we show that mitochondrial acetyl-CoA is shunted to ketogenesis, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived β-hydroxybutyrate (BHB) is stocked in CD8+ Tm cells, which epigenetically modifies H3K9 of FoxO1 and PGC-1α with β-hydroxybutyrylation so to upregulate these genes expression. As a result, FoxO1 and PGC-1α cooperatively upregulates Pck1 expression, thus directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results unveil that the ketogenesis acts as an unusual metabolic pathway in CD8+ Tm cells, linking epigenetic modification required for memory development.
2019-04-13 | GSE129723 | GEO