Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Hepatic Gene Expression Changes in Diethynitrosamin-initiated and Cholic Acid promoted tumors

ABSTRACT: Mice were fed with either normal diet (ND), 0.2% cholic acid diet (0.2%CA), DEN treated and fed ND or DEN treated and fed 0.2%CA diet. DEN was treated at 15 microgram/kg body weight at postnatal day 15. Diets were fed for two months starting 8 months of age till 10 months of age. Livers were collected at10 months of age, Total RNA was isolated and used for microarray experiments. 4 groups [ND, 0.2%CA, DEN+ND and DEN+0.2%CA], pooled livers from 3-5 mice

ORGANISM(S): Mus musculus

SUBMITTER: Udayan Apte

PROVIDER: E-GEOD-75445 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling.

Sun Lina L Beggs Kevin K Borude Prachi P Edwards Genea G Bhushan Bharat B Walesky Chad C Roy Nairita N Manley Michael W MW Gunewardena Sumedha S O'Neil Maura M Li Hua H Apte Udayan U

American journal of physiology. Gastrointestinal and liver physiology 20160505 1

Hepatocellular carcinoma (HCC) is the most common hepatic malignancy and the third leading cause of cancer related deaths. Previous studies have implicated bile acids in pathogenesis of HCC, but the mechanisms are not known. We investigated the mechanisms of HCC tumor promotion by bile acids the diethylnitrosamine (DEN)-initiation-cholic acid (CA)-induced tumor promotion protocol in mice. The data show that 0.2% CA treatment resulted in threefold increase in number and size of DEN-induced liver ...[more]

PMID: 27151938

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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.

Dataset Information

Hepatic Gene Expression Changes in Diethynitrosamin-initiated and Cholic Acid promoted tumors

Publications

Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling.

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