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.

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.

Project description:Our objective was to examine risk factors associated with development of nonalcoholic fatty liver disease (NAFLD) among women with endometrial cancer who underwent surgical staging with or without oophorectomy.This is a retrospective study that evaluated endometrial cancer cases that underwent surgical staging (n = 666) and endometrial hyperplasia cases that underwent hysterectomy-based treatment (n = 209). This study included 712 oophorectomy cases and 163 nonoophorectomy cases. Archived records were reviewed for participant demographics, medical comorbidities, operative notes, histology results, and radiology reports for NAFLD. Cumulative risks of NAFLD after surgical operation were correlated to demographics and medical comorbidities.The cumulative prevalence of NAFLD in 875 women with endometrial tumor was 14.1%, 20.5%, and 38.4% at 1, 2, and 5 years after surgical operation, respectively. On multivariate analysis, after controlling for age, ethnicity, body mass index, medical comorbidities, tumor type, hormonal treatment pattern, and oophorectomy status, age younger than 40 years (2-y cumulative prevalence, 26.6% vs 16.8%; hazard ratio [HR], 1.85; 95% CI, 1.27-2.71; P = 0.001) and age 40 to 49 years (2-y cumulative prevalence, 23.1% vs 16.8%; HR, 1.49; 95% CI, 1.08-2.04; P = 0.015) remained significant predictors for developing NAFLD after surgical operation compared with age 50 years or older. Oophorectomy was an independent predictor for increased risk of NAFLD (20.9% vs 15.9%; HR, 1.70; 95% CI, 1.01-2.86; P = 0.047). In addition, NAFLD was significantly associated with postoperative development of diabetes mellitus (39.2% vs 15.3%; HR, 2.26; 95% CI, 1.52-3.35; P < 0.0001) and hypercholesterolemia (34.3% vs 17.5%; HR, 1.71; 95% CI, 1.12-2.63; P = 0.014).Oophorectomy in young women with endometrial cancer significantly increases the risk of NAFLD. This is associated with development of diabetes mellitus and hypercholesterolemia after oophorectomy.

Dataset Information

Increased PD-L1 Restricts Liver Injury in Nonalcoholic Fatty Liver Disease.

Publications

Increased PD-L1 Restricts Liver Injury in Nonalcoholic Fatty Liver Disease.

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