Gene Expression in mice liver after knockdown of Rab5
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67227 | GEO | 2015/05/03
SECONDARY ACCESSION(S): PRJNA279290
REPOSITORIES: GEO
Similar Datasets
Project description:RNAi-mediated silencing of Rab5 and the consequent loss of endosomes in the mouse liver caused severe metabolic defects such as hypoglycemia, hepatomegaly, hypercholesterolemia, hyperlipidemia and glycogen accumulation. Gene expression in mice liver after knockdown of Rab5 has been performed the Mouse Genome 430 2.0 microarrays to identify biological processes and pathways affected by Rab5. The mice received either PBS or lipid nanoparticles (LNPs) loaded with siRNAs agains Rab5all or Luciferase control at 1.5 mg/kg via tail vein injection. At 5 day post injection mice were sacrificed using cervical dislocation and liver tissue was harvested, snap frozen in liquid nitrogen for RNA isolation; Gene expression studies were performed applying the Mouse Genome 430 2.0 microarrays.
2015-05-03 | E-GEOD-67227 | biostudies-arrayexpress
Project description:Autophagy is a lysosomal degradation process involved in the turnover of organelles or other cell constituents, in providing sources for energy production under starving conditions, and in cell metabolism. A key protein in the macroautophagic machinery is the autophagy related protein (Atg) 7. Constitutive deletion of Atg7 is lethal at birth. A conditional deletion of Atg7 in hepatocytes leads to hepatomegaly and in aged animals to liver tumors. With this study, we aimed at analyzing the hepatomegaly development more detailed. The 3- to 4-fold enlargement of the liver takes place between day 25 and 35 after birth (P25-P35) and persists at least until P90. This is accompanied by a change in the expression of enzymes involved in the glycogen/glucose metabolism. While glycogen synthesis is inhibited, glucose is preferentially kept as glucose-6-phosphate inside the cells, inducing a swelling of the cells caused by hyperosmolarity. An increase of lipogenic enzymes suggests that glucose-6-phosphate is delivered to lipogenic pathways, which is supported by the occurrence of a steatosis around P30. The development of hepatomegaly is accompanied by a polyploidisation of hepatocytes, an enhanced expression of genes related to inflammatory processes, and an infiltration of macrophages. Our data provide evidence that the attenuation of macroautophagy in hepatocytes leads to a glucose retention which causes cell swelling. The resulting hepatomegaly, which develops in a time interval of about 10 days, perturbs liver perfusion and induces an inflammatory reaction together with polyploidisation.
2016-07-12 | E-MTAB-4389 | biostudies-arrayexpress
Project description:Endosomal trafficking plays an integral role in various eukaryotic cell activities. In animal cells, a member of the RAB GTPase family, RAB5, is known as a key regulator of various endosomal functions, which include endosomal fusion, endosomal signaling, and endosomal motility. In addition to orthologs of animal RAB5, plants harbor the plant-unique RAB5 group, ARA6 group, which is conserved in all land plant lineages. The Arabidopsis genome encodes three RAB5 members: two conventional type RAB5 (ARA7 and RHA1) and one plant-specific ARA6. It has been already reported that ARA6 mediates a trafficking pathway from endosomes to the plasma membrane, and also shown to be involved in salt stress tolerance and flowering. However, physiological functions of ARA6 and their detailed mechanism are still remained elusive. In this study, we carried out a microarray analysis of the ara6-1 mutant. Possible involvement of ARA6 in sugar metabolism will be reported. The transcriptional profiling between the wild-type Col. and a RAB5 knock out mutant, ara6-1.
2015-02-18 | E-GEOD-57013 | biostudies-arrayexpress
Project description:abstract1: Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have previously shown that the activity of Carbohydrate Response Element Binding Protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia. In the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. PMID : 32083759 Abstract2:Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC) activity, which induces severe hepatomegaly and increases the risk for liver cancer in patients. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor that has been proposed as a pro-oncogenic molecular switch that supports tumour progression. Here we studied the contribution of ChREBP signalling on liver disease progression and tumour susceptibility in a mouse model for GSD Ia. Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. Hepatic ChREBP normalization induced dysplastic liver growth, massively increased hepatocyte size and sensitized to hepatic inflammation and liver fibrosis in GSD Ia mice. Furthermore, the nuclear levels of the oncoprotein YAP were increased and its transcriptional targets were induced in ChREBP normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while chromosomal instability, cGAS-STING pathway, senescence, and hepatocyte dedifferentiation gene signatures emerged. Upon ChREBP silencing in immortalized human hepatocytes, on the other hand, the induction of YAP target gene expression was paralleled by cell cycle arrest, cell death, and reduced proliferation. In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while protecting against liver disease progression and hepatocellular tumour induction in GSD Ia. These results underline the importance to establish the context-specific roles of ChREBP to define its therapeutic potential. PMID:37085901
2023-04-22 | GSE143357 | GEO
Project description:Glycogen storage disease type 1a (GSD-1a) is an autosomal recessive disorder caused by mutations in the catalytic subunit of the glucose-6-phosphatase-alpha (G6Pase-α). The current treatment of GSD-1a is based on the control of symptomatic hypoglycemia. Long-term complications such as renal failure and development of hepatocellular adenoma/carcinoma develop in the majority of patients. The aim of this study was to determine the proteomic expression changes in the liver of LS-G6pc-/- mice, a mouse model of GSD-1a, in comparison with wild type mice to identify potential biomarkers of the pathophysiology of the affected liver.
2019-11-25 | PXD011561 | Pride
Project description:Endosomal trafficking plays integral roles in various eukaryotic cell activities. In animal cells, a member of the RAB GTPase family, RAB5, is a key regulator of various endosomal functions. In addition to orthologs of animal RAB5, plants harbor the plant-specific RAB5 group, the ARA6 group, which is conserved in land plant lineages. In Arabidopsis thaliana, ARA6 and conventional RAB5 act in distinct endosomal trafficking pathways; ARA6 mediates trafficking from endosomes to the plasma membrane, whereas conventional RAB5 acts in endocytic and vacuolar trafficking pathways. ARA6 is also required for normal salt and osmotic stress tolerance, although the functional link between ARA6 and stress tolerance remains unclear. In this study, we investigated ARA6 function in stress tolerance by monitoring broad-scale changes in gene expression in the ara6 mutant. A comparison of the expression profiles between wild-type and ara6‐1 plants revealed that the expression of the Qua-Quine Starch (QQS) gene was significantly affected by the ara6‐1 mutation. QQS is involved in starch homeostasis, consistent with the starch content decreasing in the ara6 mutants to approximately 60% of that of the wild-type plant. In contrast, the free and total glucose content increased in the ara6 mutants. Moreover, the proliferation of Pseudomonas syringae pv. tomato DC3000 was repressed in ara6 mutants, which could be attributed to the elevated sugar content. These results suggest that ARA6 is responsible for starch and sugar homeostasis, most probably through the function of QQS.
2015-02-18 | GSE57013 | GEO
Project description:Complement promotes vascular inflammation in transplant organ rejection and connective tissue diseases. Here we identify ZFYVE21 as a complement-induced Rab5 effector that regulates pro-inflammatory non-canonical NF-B signaling in endothelial cells (EC). In response to membrane attack complexes (MAC), ZFYVE21 is post-translationally stabilized via recruitment to MAC+Rab5+ endosomes in a Rab5- and PI(3)P-dependent manner. ZFYVE21 promotes SMURF2-mediated polyubiquitinylation and proteasome-dependent degradation of endosome-associated PTEN to induce vesicular enrichment of PI(3,4,5)P3 and sequential recruitment of activated Akt and NF-B-inducing kinase (NIK). Pharmacologic alteration of the phosphoinositide content of MAC+Rab5+ endosomes with miltefosine reduces ZFYVE21 induction, EC activation, as well as allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC- but not ligand-induced non-canonical NF-B and is a biomarker for complement-mediated endothelial signaling in human renal and synovial tissues. Our data identifies ZFYVE21 as a novel Rab5 effector, defines a Rab5-ZFYVE21-SMURF2-pAkt axis by which it mediates EC activation, and demonstrates a role for this pathway as a drug target and biomarker for complement-mediated pathologies.
2019-04-09 | PXD013381 | Pride
Project description:We report the results of AcH3K9 ChIP-Seq on regenerating liver harvested 12 h after partial hepatectomy (PH) from mice treated with supplemental parenteral dextrose (to delay onset of PH-induced hypoglycemia) or vehicle (as control). Examination of the effect of delaying PH-induced hypoglycemia on histone H3K9 acetylation in regenerating liver.
2016-02-09 | E-GEOD-71496 | biostudies-arrayexpress
Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
2024-02-22 | GSE234232 | GEO
Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
2024-02-22 | GSE234233 | GEO