Dorn, Christoph and Engelmann, Julia C. and Saugspier, Michael and Koch, Andreas and Hartmann, Arndt and Mueller, Martina and Spang, Rainer and Bosserhoff, Anja and Hellerbrand, Claus (2014) Increased expression of c-Jun in nonalcoholic fatty liver disease. LABORATORY INVESTIGATION, 94 (4). pp. 394-408. ISSN 0023-6837, 1530-0307
Full text not available from this repository. (Request a copy)Abstract
Overnutrition is the major cause of nonalcoholic fatty liver disease (NAFLD) and its advanced form nonalcoholic steatohepatitis (NASH). We aimed to develop and characterize a nnurine model, which resembles both the pathology and nutritional situation, of NASH patients in Western societies. Mice were fed with a NASH-inducing diet (ND) containing sucrose, cholesterol and fats rich in saturated fatty acids in a composition, which mimics Western food. After 12 weeks, ND-fed mice revealed obesity and impaired glucose tolerance. In the liver, ND-feeding led to marked steatosis, hepatocellular damage, inflammation and beginning fibrosis. Transcriptome-wide gene expression analysis and search for over-represented transcription factor target sites among the differentially expressed genes identified activator protein-1 (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 as hub in the largest connected deregulated sub-network in ND livers. Accordingly, ND livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun expression was enhanced in ND-fed mice. Combined tissue microarray technology and imnnunohistochemical analysis confirmed enhanced hepatic c-Jun levels in NAFLD patients, which correlated with inflammation, and notably, with the degree of hepatic steatosis. In summary, our new 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATOCELLULAR-CARCINOMA; THERAPEUTIC IMPLICATIONS; HEPATIC INFLAMMATION; INSULIN-RESISTANCE; GENE-EXPRESSION; OBESE-PATIENTS; STEATOHEPATITIS; JNK; FIBROSIS; PATHOGENESIS; AP-1; c-Jun; metabolic syndrome; NAFLD; NASH |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I Medicine > Lehrstuhl für Pathologie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Statistische Bioinformatik (Prof. Spang) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Nov 2019 10:35 |
| Last Modified: | 15 Nov 2019 10:35 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10408 |
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