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:ImportanceThe onset age of nonalcoholic fatty liver disease (NAFLD) is decreasing, and whether earlier ages of NAFLD onset are associated with increased cancer risk is currently unclear.ObjectiveTo explore the association between NAFLD new-onset age and cancer risk.Design, setting, and participantsThis cohort study was conducted among 179 328 participants included in the Kailuan Cohort Study between 2006 and 2021. In total, 46 100 incident NAFLD cases were identified. For each case, a participant matched by age (older or younger by 1 year) and sex was randomly selected to create a new matched study cohort. Data were analyzed from December 2022 through April 2023.ExposureOnset of NAFLD.Main outcomes and measuresThe association between the onset age of NAFLD and the risk of different cancer types was evaluated using weighted Cox regression models. Population-attributable fractions (PAFs) were used to quantify the association of NAFLD with cancer risk at different ages.ResultsAmong 63 696 participants (mean [SD] age, 51.37 [12.43] years; ‭10 932 females [17.2%] and ‭52 764 males [82.8%]), 31 848 individuals had NAFLD and 31 848 individuals were in the control group. During a median (IQR) follow-up of 10.16 (7.89-11.67) years, 2415 patients were diagnosed with cancer. Compared with the matched group, patients aged less than 45 years at NAFLD onset exhibited a higher risk of cancer (average hazard ratio [AHR], 1.52; 95% CI, 1.09-2.12), and as the onset age of NAFLD increased, the cancer risk decreased (ages 45-54 years: AHR, 1.50; 95% CI, 1.15-1.97; ages 55-64 years: AHR, 1.13; 95% CI, 0.97-1.33; ages >65 years: AHR, 0.75; 95% CI, 0.45-1.27; P for interaction < .001). Among patients aged less than 45 years at NAFLD onset, cancers were mainly digestive system and lung cancers, with AHR values of 2.00 (95% CI, 1.08-3.47) and 2.14 (95% CI, 1.05-4.36), respectively. PAFs also showed that in patients aged less than 45 years at NAFLD onset, 17.83% (95% CI, 4.92%-29.86%) of cancer risk was attributable to NAFLD.‬‬‬‬.Conclusions and relevanceThis study found that NAFLD was associated with increased cancer risk and there was an interaction with onset age, such that the younger the onset age of NAFLD, the greater the cancer risk.

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.

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Surgical menopause and increased risk of nonalcoholic fatty liver disease in endometrial cancer.

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Surgical menopause and increased risk of nonalcoholic fatty liver disease in endometrial cancer.

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