Peroxisomes and mitochondria are dysfunctional in obese diabetic (db/db) mice with fatty liver
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE59930 | GEO | 2015/03/23
SECONDARY ACCESSION(S): PRJNA257074
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose: MetS consist of five risk factors: elevated blood pressure and fasting glucose, visceral obesity, dyslipidemia and hypercholesterinemia. The physiological impact of lipid metabolism indicated as visceral obesity and hepatic lipid accumulation is still under debate. One major cause of disturbed lipid metabolism might be dysfunction of cellular organelles controlling energy homeostasis, i.e. mitochondria and peroxisomes. Experimental design: The New Zealand Obese (NZO) mouse model exhibits a polygenic syndrome of obesity, insulin resistance, triglyceridemia and hypercholesterolemia that resembles human metabolic syndrome. We applied a combinatorial approach of lipidomics with liver transcriptomics, 2D-DIGETM and mass spectroscopy based organelle proteomics of highly purified mitochondria and peroxisomes in male mice, to investigate molecular mechanisms related to the impact of lipid metabolism in the pathophysiology of the metabolic syndrome. Conclusions and clinical relevance: Proteome analyses of liver organelles indicated differences in fatty acid metabolism, oxidative stress and response, mainly influenced by PG-C1α/PPARα mediated pathways. These results were in accordance with serum lipid profiles and elevated organelle functionality. These data emphasize that metabolic syndrome is accompanied with increased mitochondria and peroxisomal activity controlling directly cellular energy homeostasis to cope with dyslipidemia and hypercholesterinemia driven hepatic lipid overflow in developing a fatty liver.
2017-11-01 | GSE95489 | GEO
Project description:A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further used for functional enrichment analysis and network analysis to identify biological processes and pathways differentially regulated in the db/db nerve. Expression profile clustering was performed to identify co-expressed DEGs. A set of co-expressed lipid metabolism genes was used for promoter sequence analysis.We identified 4,017 DEGs; 2,122 genes were up-regulated and 1,895 genes were down-regulated in the db/db relative to the db+ samples. Over-represented biological processes identified by the functional enrichment analysis include cell cycle, lipid metabolic process, lipid transport, carbohydrate metabolic process, response to stress, apoptosis, axonogenesis and cell adhesion. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, PPAR signaling, apoptosis, and axon guidance. The majority of DEGs in the glycolysis, TCA cycle, oxidative phosphorylation, fatty acid metabolism, glycerolipid metabolism, mitochondrial fatty acid elongation, lipid transport, adipocytokine signaling, PPAR signaling, and apoptosis pathways are up-regulated, whereas most of the axonogenesis-related genes are down-regulated in db/db nerve. A network of DEGs based on their co-citation in literature identified regulatory relationship between Tnf-α and key genes from the regulated pathways. Promoter sequence analysis identified over-represented transcription factor binding site (TFBS) motifs in the promoter regions of twenty two co-expressed lipid metabolism-related genes suggesting coordinated regulation of these genes by multiple transcription factors (TF). Furthermore, TF binding to these TFBS and differentially regulated in our data are annotated with nervous system development and immune response suggesting possible co-regulation of lipid metabolism, nervous system development and stress response genes. Gene expression changes in our data are consistent with pathological characteristics observed in DN including axon degeneration and demyelination, and support existing hypotheses regarding hyperglycemia mediated nerve damage in DN. Our findings support the role of hyperglycemia-induced oxidative stress and ischemia in nerve injury. Our results also support the hypothesis of oxidized lipid-mediated nerve injury and increased mitochondrial oxidative stress in dyslipidemia. Moreover, our analyses revealed a possible co-regulation mechanism connecting hyperlipidemia, stress response and axonal degeneration. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes
2011-02-18 | E-GEOD-27382 | biostudies-arrayexpress
Project description:The mechanisms of diabetic neuropathy (DN) development and progression are not fully understood. We examined global gene expression in the sciatic nerve (SCN) of BKS-db/db mice at 8 and 24 weeks of age to identify genetic pathways altered in peripheral nerves at early and advanced stages of DN. The sets of differentially expressed genes were analyzed to identify enriched biological functions and regulated genetic pathways. Our results suggest that carbohydrate metabolism and lipid metabolism pathways are dysregulated in the db/db SCN at 8 weeks of age. Impairment of Schwann cell-extracellular matrix interaction and axon guidance occurs early in the development of DN, while neurotrophic support, neurotransmitter transport and axonogenesis are impaired at the advanced stage of DN. Gene expression changes also suggest that oxidative stress- and inflammation-mediated nerve damage occurs by 8 weeks. Our analysis identified mechanisms regulated in the early stages of DN. Additionally, interactions between genes from different pathways provide insight into potential relationships among the regulated pathways. RNA extracted from the SCN of four groups of mice: (8 week old db/db (n=8) or db/+ (n=8), and 24 week old db/db (n=6) or db/+ (n=7)) was hybridized to Affymetrix GeneChip microarrays. Gene expression for the two genotypes (db/db vs. db/+) was compared at each age. Gene expression at the early and advanced stages of DN (8 weeks vs. 24 weeks) was also compared for each genotype.
2012-01-06 | E-GEOD-34889 | biostudies-arrayexpress
Project description:The mechanisms of diabetic neuropathy (DN) development and progression are not fully understood. We examined global gene expression in the sciatic nerve (SCN) of BKS-db/db mice at 8 and 24 weeks of age to identify genetic pathways altered in peripheral nerves at early and advanced stages of DN. The sets of differentially expressed genes were analyzed to identify enriched biological functions and regulated genetic pathways. Our results suggest that carbohydrate metabolism and lipid metabolism pathways are dysregulated in the db/db SCN at 8 weeks of age. Impairment of Schwann cell-extracellular matrix interaction and axon guidance occurs early in the development of DN, while neurotrophic support, neurotransmitter transport and axonogenesis are impaired at the advanced stage of DN. Gene expression changes also suggest that oxidative stress- and inflammation-mediated nerve damage occurs by 8 weeks. Our analysis identified mechanisms regulated in the early stages of DN. Additionally, interactions between genes from different pathways provide insight into potential relationships among the regulated pathways.
2012-01-06 | GSE34889 | GEO
Project description:A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further used for functional enrichment analysis and network analysis to identify biological processes and pathways differentially regulated in the db/db nerve. Expression profile clustering was performed to identify co-expressed DEGs. A set of co-expressed lipid metabolism genes was used for promoter sequence analysis.We identified 4,017 DEGs; 2,122 genes were up-regulated and 1,895 genes were down-regulated in the db/db relative to the db+ samples. Over-represented biological processes identified by the functional enrichment analysis include cell cycle, lipid metabolic process, lipid transport, carbohydrate metabolic process, response to stress, apoptosis, axonogenesis and cell adhesion. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, PPAR signaling, apoptosis, and axon guidance. The majority of DEGs in the glycolysis, TCA cycle, oxidative phosphorylation, fatty acid metabolism, glycerolipid metabolism, mitochondrial fatty acid elongation, lipid transport, adipocytokine signaling, PPAR signaling, and apoptosis pathways are up-regulated, whereas most of the axonogenesis-related genes are down-regulated in db/db nerve. A network of DEGs based on their co-citation in literature identified regulatory relationship between Tnf-α and key genes from the regulated pathways. Promoter sequence analysis identified over-represented transcription factor binding site (TFBS) motifs in the promoter regions of twenty two co-expressed lipid metabolism-related genes suggesting coordinated regulation of these genes by multiple transcription factors (TF). Furthermore, TF binding to these TFBS and differentially regulated in our data are annotated with nervous system development and immune response suggesting possible co-regulation of lipid metabolism, nervous system development and stress response genes. Gene expression changes in our data are consistent with pathological characteristics observed in DN including axon degeneration and demyelination, and support existing hypotheses regarding hyperglycemia mediated nerve damage in DN. Our findings support the role of hyperglycemia-induced oxidative stress and ischemia in nerve injury. Our results also support the hypothesis of oxidized lipid-mediated nerve injury and increased mitochondrial oxidative stress in dyslipidemia. Moreover, our analyses revealed a possible co-regulation mechanism connecting hyperlipidemia, stress response and axonal degeneration.
2011-02-18 | GSE27382 | GEO
Project description:In non-alcoholic fatty liver disease (NAFLD) caused by ectopic lipid accumulation, lipotoxicity is a crucial molecular risk factor. Mechanisms to eliminate lipid overflow can prevent the liver from functional complications. This may involve increased secretion of lipids or metabolic adaptation to ß-oxidation in lipid-degrading organelles such as mitochondria and peroxisomes. In addition to dietary factors, increased plasma fatty acid levels may be due to increased triglyceride synthesis, lipolysis, as well as de novo lipid synthesis (DNL) in the liver. In the present study, we investigated the impact of fatty liver caused by elevated DNL, in a transgenic mouse model with liver-specific overexpression of human sterol regulatory element-binding protein-1c (alb-SREBP-1c), on hepatic gene expression, on plasma lipids and especially on the proteome of peroxisomes by omics analyses, and we interpreted the results with knowledge-based analyses. In summary, the increased hepatic DNL is accompanied by marginal gene expression changes but massive changes in peroxisomal proteome. Furthermore, plasma phosphatidylcholine (PC) as well as lysoPC species were altered. Based on these observations, it can be speculated that the plasticity of organelles and their functionality may be directly affected by lipid overflow.
2019-10-15 | GSE132298 | GEO
Project description:The aim of this project was to profile the proteome of mouse-derived serum in order to identify those that showed significant quantitative different proteins among leptin-deficient (db/db) mouse, the genetic non-alcoholic fatty liver disease (NAFLD) mouse model and their lean bks mouse group.
2022-10-14 | PXD027937 | Pride
Project description:The aim of this project was to profile the proteome of mouse-derived liver in order to identify those that showed significant quantitative different proteins among leptin-deficient (db/db) mouse, the genetic non-alcoholic fatty liver disease (NAFLD) mouse model and their lean BKS mouse group.
2022-10-14 | PXD027938 | Pride
Project description:Nonalcoholic fatty liver disease (NAFLD) is a common disorder in obese people and is becoming the leading cause of hepatocellular carcinoma (HCC). Recently, lncRNAs have been proven to play remarkable roles in numerous biological processes and human diseases, including NAFLD. However, the function of lncRNA in NAFLD pathogenesis remains largely unknown. The aim of this study was to explore the lncRNA expression profile in NAFLD mice and to identify novel lncRNAs involved in the pathogenesis of NAFLD. We performed microarray analysis to compare the expression profiles of lncRNAs and mRNAs in the liver of diabetic db/db mice with NAFLD and normal mice.
2017-12-19 | GSE108228 | GEO
Project description:Fenofibrate lowers cardiac lipid accumulation and attenuates diabetic cardiomyopathy in db/db mice.
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