Gene expression signatures for GP73-induced non-obese nonalcoholic fatty liver disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE163918 | GEO | 2020/12/29
REPOSITORIES: GEO
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Project description:Nonalcoholic fatty liver disease (NAFLD) is the most prevalent hepatic pathology worldwide. However, the precise molecular mechanisms for NAFLD are still not sufficiently explained. Recently, a new mode of cell death (cuproptosis) is found. However, the relationship between NAFLD and cuproptosis remains unclear. We analyzed three public datasets to identify cuproptosis-related genes stably expressed in NAFLD. Then, we performed a series of bioinformatics analyses to explore the relationship between NAFLD and cuproptosis-related genes. Finally, 3 normal control mouse and 3 high-fat diet (HFD)-induced NAFLD C57BL/6J mouse models were established to carry out transcriptome analysis.
2023-04-30 | E-MTAB-11980 | biostudies-arrayexpress
Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.
2023-03-23 | PXD040233 | Pride
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Project description:Whole genome expression profilling were undertaken in high fat diet (HFD)-fed obese rats to identify the genetic factors associated with metabolic dysfunction, insulin resistance and obesity. Sprague dawley male rats were maintained on HFD for 12 weeks ad libitum regimen. Liver being the principal organ for glucose homeostasis is targeted for microarray profilling. We could identify genes/factors associated with obesity induced metabolic dysfunction. Custom Rat Whole Genome 8x60k Gene Expression Microarray (AMADID:030192 ) designed by Genotypic Technology Private Limited.
2016-07-01 | E-GEOD-48794 | biostudies-arrayexpress
Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.
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Project description:BACKGROUND AND AIMS: It is proposed that impaired expansion of subcutaneous adipose tissue (SAT), caused in part by an increase in adipose tissue fibrosis, redirects fatty acids to the liver and other organs, leading to ectopic lipid accumulation and insulin resistance. We therefore evaluated whether a decrease in SAT expandability, assessed by measuring SAT lipogenesis (triglyceride production), and an increase in SAT fibrogenesis (collagen production) are associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance in people with obesity. APPROACH AND RESULTS: In vivo SAT lipogenesis and fibrogenesis, the expression of SAT genes involved in extracellular matrix (ECM) formation, and insulin sensitivity were assessed in three groups stratified by adiposity, insulin sensitivity and intrahepatic triglyceride (IHTG) content: 1) healthy lean (Lean-NL; n=12); 2) obese with normal IHTG content and normal glucose tolerance (Ob-NL; n=25); and 3) obese with NAFLD and abnormal glucose metabolism (Ob-NAFLD; n=25). Abdominal SAT total triglyceride synthesis rates were greater in the Ob-NL (65.9±4.6 g/wk) and Ob-NAFLD (71.1±6.7 g/wk) than the Lean-NL group (16.2±2.8 g/wk), without a difference between the obese groups. Abdominal SAT collagen synthesis rate and the composite expression of collagen genes progressively increased from Lean-NL to Ob-NL to Ob-NAFLD and were greater in the Ob-NAFLD than the Ob-NL group (P<0.05). Collagen synthesis rate and the composite expression of collagen genes correlated with factors that regulate collagen production, including circulating insulin and fibrogenic factors in SAT (all P<0.001). CONCLUSIONS: Adipose tissue lipogenesis and expandability are not impaired in people with obesity and NAFLD. However, SAT fibrogenesis and extracellular matrix remodeling are greater in people with obesity and NAFLD than in those with obesity and normal IHTG content. ClinicalTrials.gov number: NCT02706262.
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Project description:Male C57BL/6J mice were fed a high-fat diet (HFD, 60 kcal% fat, D12492, Research Diets, Inc) or normal standard chow diet with 10 kal% fat (ND, D09100304, Research Diets, Inc). Specifically, 6-week-old mice were fed a HFD for 12 weeks to induce insulin resistance (HFD-12w group); 14-week-old mice were fed a HFD for 4 weeks to induce obesity (HFD-4w group). Control mice were fed a ND continuously for 12 weeks starting at 6 weeks of age (ND group). All mice reached the experimental endpoint at 18 weeks of age. Insulin sensitivity was measured by glucose tolerance test and insulin tolerance test. Mice that developed insulin resistance in HFD-12w group and obese mice with normal insulin sensitivity in HFD-4w group were used for further experiments. Mice in ND group were used as controls. Upon reaching the experimental endpoint, livers from three insulin-resistant mice, three insulin-sensitive obese mice, and three control mice were removed for RNA sequencing.
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