Rat (Wistar) Liver CDAA Diet 4-8-12 Weeks Ensembl84 (BIBC)
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE134715 | GEO | 2020/01/27
REPOSITORIES: GEO
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Project description:Nonalcoholic steatohepatitis (NASH) is a major cause of liver fibrosis with increasing prevalence worldwide. Currently there are no approved drugs available. The development of new therapies is difficult as diagnosis and staging requires biopsies. Consequently, predictive plasma biomarkers would be useful for drug development. To identify new plasma biomarkers in a choline-deficient L-amino acid-defined diet rat NASH model we analyzed liver and plasma samples by proteomics, revealing disease relevant signatures and a high correlation between liver mRNA and protein changes. We developed a multi-dimensional attribute ranking approach integrating multi-omics data with liver histology and prior knowledge uncovering known human markers, but also novel candidates. Using regression analysis, we show that the top-ranked plasma markers were highly predictive for fibrosis in our model and hence can serve as preclinical plasma biomarkers. Our approach presented here illustrates the power of multi-omics analyses combined with plasma proteomics and is readily applicable to human biomarker discovery.
2020-01-28 | PXD014751 | Pride
Project description:Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient (MCD) + high fat (HF) diet with or without 0.1% metformin for 8 weeks.
2012-02-21 | E-GEOD-35961 | biostudies-arrayexpress
Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.
2010-09-09 | E-GEOD-24031 | biostudies-arrayexpress
Project description:Nonalcoholic Fatty Liver Disease (NAFLD) is a broad spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. The choline-deficient L-amino acid-defined (CDAA) diet-induced NAFLD animal model has traditionally been used to understand the molecular mechanisms of disease development and progression. Although this animal model shows a similar course of disease progression to human NAFLD, it does not develop comorbidities such as obesity and type 2 diabetes. Therefore, its relevance to human NAFLD (what aspects of the disease etiology are recapitulated in this model?) is not fully understood. We applied microarray analysis to characterize its pathophysiology, and evaluate the similarity across species.
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Project description:Liver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. LSEC play a pivotal role in liver fibrogenesis in the CDAA dietary model of non-alcoholic steatohepatitis (NASH). We used microarrays to analyse the program of gene expression in murine liver endothelial cells after 10 weeks of CDAA diet.
2020-09-15 | GSE140994 | GEO
Project description:Sphingomyelin synthase (SMS)–related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) molecule that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency–mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr knock out (KO) and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency-mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructoseinduced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PEPLC deficiency or PE supplementation effectively prevented membrane-bound βcatenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine (PC) ratios, and that human plasma PE levels are negatively associated with TNF-α and TGFβ1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.
2023-08-17 | GSE241036 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes but their molecular pathogenesis is not fully elucidated. Global RNA sequencing of snap frozen liver tissue from 98 patients with biopsy-proven NAFLD was performed. Unsupervised hierarchical clustering well-distinguished NASH from NAFL, and NASH patients exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified multiple secreted proteins upregulated in NASH and/or advanced fibrosis
2021-05-31 | GSE167523 | GEO
Project description:The lack of a preclinical model of nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC) that recapitulates human disease is a major barrier to therapeutic development. We report a high fat-high sugar diet-induced NASH and HCC in a stable isogenic 129S1/SvImJ crossed with C57Bl/6J mice. Following diet initiation, there was sequential development of steatosis (4-8 weeks), steatohepatitis with ballooning and Mallory-Denk bodies (12-16 weeks), progressive fibrosis (16 week onwards) and spontaneous HCC (32-52 weeks). The mice developed obesity, insulin resistance and dyslipidemia. There was concordance with the human NASH transcriptome (FDR 0.001) with activation of lipogenic, inflammatory and apoptotic pathways relevant in humans. The HCC gene signature resembled S1 and S2 human HCC subclass (FDR 0.01 for both). This simple model of NASH and HCC that resembles human disease in terms of its triggers, physiological and biochemical parameters, histology, transcriptomic profile, and outcomes can facilitate preclinical development for these conditions. 129S1/SvImJ;C57Bl/6J (129/B6) mice were fed with high-fat diet (Western Diet) and high fructose-glucose solution (Sugar Water) (WD SW) or chow diet (CD) for 8 weeks, and total RNA samples were isolated from liver tissues for genome-wide expression profiling.
2016-07-25 | E-GEOD-67678 | biostudies-arrayexpress
Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array
2010-09-09 | GSE24031 | GEO
Project description:The lack of a preclinical model of nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC) that recapitulates human disease is a major barrier to therapeutic development. We report a high fat-high sugar diet-induced NASH and HCC in a stable isogenic 129S1/SvImJ crossed with C57Bl/6J mice. Following diet initiation, there was sequential development of steatosis (4-8 weeks), steatohepatitis with ballooning and Mallory-Denk bodies (12-16 weeks), progressive fibrosis (16 week onwards) and spontaneous HCC (32-52 weeks). The mice developed obesity, insulin resistance and dyslipidemia. There was concordance with the human NASH transcriptome (FDR 0.001) with activation of lipogenic, inflammatory and apoptotic pathways relevant in humans. The HCC gene signature resembled S1 and S2 human HCC subclass (FDR 0.01 for both). This simple model of NASH and HCC that resembles human disease in terms of its triggers, physiological and biochemical parameters, histology, transcriptomic profile, and outcomes can facilitate preclinical development for these conditions. 129S1/SvImJ;C57Bl/6J (129/B6) mice were fed with high-fat diet (Western Diet) and high fructose-glucose solution (Sugar Water) (WD SW) or chow diet (CD) for 52 weeks, and total RNA samples were isolated from liver and tumor tissues for genome-wide expression profiling.
2016-07-25 | E-GEOD-67679 | biostudies-arrayexpress