Hepatic transcriptomic analyses revealing the molecular pathogenesis of T2DM associated NAFLD in the ZDF rats
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ABSTRACT:
PROVIDER: PRJNA482127 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7547676_1.fastq.gz | Fastqsanger.gz | |||
| SRR7547676_2.fastq.gz | Fastqsanger.gz | |||
| SRR7547677_1.fastq.gz | Fastqsanger.gz | |||
| SRR7547677_2.fastq.gz | Fastqsanger.gz | |||
| SRR7547678_1.fastq.gz | Fastqsanger.gz |
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Project description:The ZDF rat, with spontaneous homozygous mutation of the leptin receptor gene (fa/fa), is one of the widely used animal model for studying the human type 2 diabetes mellitus (T2DM). Male ZDF rats have the symptoms of obesity and insulin resistance at a young age, accompanying with impaired islet function. However, their hepatic pathogenesis is still unclear. Based on the successive observations and the transcriptomic analyses of the liver tissue at 22 weeks old, we detected the typical clinical indications of T2DM, severe hepatic metabolic remodeling and the inflammatory liver injury in the ZDF rats. The integrin linked kinase signaling, as well as the endoplasmic reticulum stress and its downstream p38 MAPK signaling, seemed to play crucial roles in it. We have proved the ZDF rats could better simulate the pathogenesis of the human T2DM associated nonalcoholic fatty liver disease (NAFLD), and provided targets and reference for future T2DM studies.
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Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes.
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Project description:Sarcopenia has been recognized as an emerging complication of type 2 diabetes mellitus (T2DM). Currently, the pathogenesis of T2DM-related sarcopenia remains unclear. The aim of this study was to investigate the molecular mechanisms and potential therapeutic targets for T2DM-related sarcopenia. In this study, a T2DM-related sarcopenia mouse model was established using db/db mice. Proteins extracted from the gastrocnemius muscles of db/db mice and littermate control db/m mice were analyzed by a 4D label-free quantitative proteomics approach. A total of 131 upregulated and 68 downregulated proteins were identified as differentially expressed proteins (DEPs). Bioinformatics analysis revealed that DEPs were significantly enriched in lipid metabolism. Protein–protein interaction network analysis revealed that six hub proteins, including ACOX1, CPT2, ECI2, ACADVL, ACADL, and ECH1, were involved in the fatty acid oxidation. The hub protein-transcription factor-miRNA network was also constructed through the NetworkAnalyst tool. Finally, the hub proteins were validated by western blotting and immunohistochemistry and further confirmed to be significantly negatively correlated with the muscle mass and grip strength. Our study suggested that lipid metabolism, especially excessive fatty acid oxidation, may be a crucial contributor to the progression of T2DM-related sarcopenia and a common cause of the interrelationship between T2DM and sarcopenia.
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Project description:Purpose: To determine the Th17 milleu in the liver during NAFLD in the context of Diet induce obesity Methods: Mice were place on a highfat diet for 20 weeks, Th17 cells were isolated from the liver by FACS sorting the TCRb+CD4+IL-17A-GFP+ cells. Single cells were separated into 6 C1 capture chips and RNA sequencing was performed at an average depth of 3 million paired-end reads (75nt) using the Illumina HiSeq 2500, with SMART-Seq2 version 2 chemistry as recommended by the manufacturer. Results: Here, we demonstrate that NAFLD progression is associated with polarization and accumulation of a unique population of inflammatory hepatic CXCR3+Th17 cells (ihTh17) in mice. Transfer of ihTh17 cells accelerated and exacerbated NAFLD pathogenesis in vivo. Notably, ihTh17 cells, compared to conventional CXCR3-Th17 cells, exhibited increased open chromatin marks in enhancer regions, increased metabolic capacity, and were able to simultaneously produce an array of proinflammatory cytokines which directly contributed to hepatocellular damage. Modulation of the CXCR3-CXCL9/10 axis and ihTh17 metabolic state was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Conclusions: In sum, our data show that the obesity-associated environment regulates Th17 cell competence towards an ihTh17 fate and that the preferential use of glycolytic pathways in ihTh17 cells promotes their inflammatory vigor and contributes to NAFLD progression.
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Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration.
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Project description:Insulin resistance and Type 2 Diabetes Mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. To identify the underlying molecular processes in preadipocytes of T2DM patients that are a characteristic of the development of T2DM, preadipocyte cell cultures were prepared from subcutaneous fat biopsies of T2DM patients and compared with age- and BMI matched control subjects. Gene expression profiling showed changed expression of transcription factors involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were down-regulated, and inflammation/apoptosis was up-regulated in T2DM preadipocytes. The down-regulation of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage. 7 T2DM preadipocyte samples and 9 age- and BMI-matched control samples were hybridized using 70-mer oligonucleotide microarrays. Samples were labeled with either Cy3 or Cy5. A total of 20 arrays were used including dye swop. Per array, a T2DM sample was hybridized with a control sample of the same gender and matched based on age and BMI. To ensure hybridization of two samples with the same gender, three T2DM (5064, 5128, 5395) and one control sample (5616) were used twice and listed as technical replicates.
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Project description:Dyslipidemia and inflammation play key roles in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. NAFLD, particularly its severe form nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease (CVD) risk. HDL (high density lipoprotein- also a CVD risk) are decreased in NAFLD but whether HDL function is abnormal in NAFLD is unknown. Furthermore, it is unknown whether dyslipidemia contributes to reduced HDL function in NAFLD and whether hepatic inflammation further impairs HDL function in patients with NASH. Therefore, the aim of this study was to investigate HDL function and to examine the effect of dyslipidemia and inflammation on HDL metabolism in patients with biopsy-proven simple steatosis (SS) and NASH. RESULTS: Compared to controls, SS and NASH subjects had significantly higher levels of plasma triglyceride, insulin, and were more insulin resistant (HOMA, P<0.05) with no differences in total cholesterol, HDL cholesterol, ApoB100 and ApoAI levels. NAFLD patients had increased production and degradation rates of both HDLc and ApoAI that resulted in their levels remaining stable. The degradation rates also were increased of other HDL proteins, including ApoAII, ApoAIV, vitamin D-binding protein, and complement 3 (all P<0.05). NAFLD patients had increased activities of LCAT and CETP, indicating altered HDL lipidation. NAFLD induced alterations in HDL metabolism were associated with reduced anti-oxidant but increased pro-inflammatory activity of HDL. However, no differences were observed in either HDL function or the kinetics of HDLc and HDL proteins between SS and NASH subjects.
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