Placebo-controlled, randomized clinical trial with repeated liver biopsies: Long-term resveratrol treatment has no clear therapeutic benefit in non-alcoholic fatty liver disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE68421 | GEO | 2016/04/30
SECONDARY ACCESSION(S): PRJNA282686
REPOSITORIES: GEO
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Project description:Background & Aims: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting non-invasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. Methods: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0?1 (mild) and F3?4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. Results: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P<.05). Methylation at FGFR2, MAT1A, and CASP1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, whereas genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and under-expressed. Conclusions: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD. Three technical replicates were included for quality control along with 35 mild NAFLD (33 unique samples) and 24 advanced NAFLD (23 unique sample). One sample per technical duplication was randomly included for a total of 56 NAFLD samples used for study.
2013-08-30 | E-GEOD-49542 | biostudies-arrayexpress
Project description:Background & Aims: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting non-invasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. Methods: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0?1 (mild) and F3?4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. Results: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P<.05). Methylation at FGFR2, MAT1A, and CASP1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, whereas genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and under-expressed. Conclusions: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD.
2013-08-30 | GSE49542 | GEO
Project description:Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice shows a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at mid-life. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life.
2008-08-05 | GSE11845 | GEO
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress
Project description:Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice shows a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at mid-life. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life. Male C57BL/6NIA mice at 11 months of age were maintained on a standard purified mouse diet (AIN-93G) for one month prior to the start of the experiment. Beginning at one year of age, SD and EOD groups were fed a standard AIN-93G diet or AIN-93G plus 0.01% or 0.04% resveratrol for the duration of the study. Three separate groups were placed on an HC diet (AIN-93G modified by the addition of hydrogenated coconut oil to provide 60% of calories from fat) or HC + 0.01% or 0.04% resveratrol 6 weeks later and remained on those diets throughout the study. SD and HC mice were fed ad libitum. EOD mice were fed ad libitum on alternate days then moved to a separate cage without food for 24 h. Food intake and body weight were measured on a weekly basis for the duration of the study.
2008-08-04 | E-GEOD-11845 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis, where treatment options are limited. As the liver secrets most of the blood plasma proteins its diseases should affect the plasma proteome. Plasma proteome profiling on 48 patients with cirrhosis or NAFLD with normal glucose tolerance or diabetes, revealed 8 significantly changing (ALDOB, APOM, LGALS3BP, PIGR, VTN, IGHD, FCGBP and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts with a 2.7-fold expression change in NAFLD and 4-fold change in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE to NAFLD and cirrhosis. DPP4 is a known drug target in diabetes. ANPEP and TGFBI are of interest because of their potential role in extracellular matrix remodeling in fibrosis.
2019-03-04 | PXD011839 | Pride
Project description:Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis, where treatment options are limited. As the liver secrets most of the blood plasma proteins, its diseases should affect the plasma proteome. Plasma Proteome Profiling of 48 patients with cirrhosis or NAFLD, revealed eight significantly changing (ALDOB, APOM, LGALS3BP, PIGR, VTN, IGHD, FCGBP and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts with a 2.7-fold expression change in NAFLD and 4-fold change in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE to NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP and LAP3, which all upregulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, Plasma Proteome Profiling can identify potential biomarkers and drug targets in liver disease.
2019-03-05 | PXD012056 | Pride
Project description:Background & Aims: Although non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, aspects of its molecular pathogenesis are unknown and clinical biomarkers for early diagnosis and accurate disease staging remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of NAFLD and explore the utility of novel candidate biomarkers in NAFLD patients. Methods: Liver protein fractions were analyzed in a relative quantitative proteomic approach utilizing isobaric tags for relative and absolute quantitation (iTRAQ) labeling combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential expression was confirmed independently by western blotting and immunohistochemistry, first in mouse sections and then in biopsies from paediatric NAFLD patients. Candidate serum biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling we identified decreased expression of hepatic glyoxalase 1 (GLO1) in an animal model of NAFLD. GLO1 protein levels were also found reduced in tissue biopsies from pediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid-loading in hepatocytes, GLO1 is first hyper-acetylated then ubiquitinylated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 62 biopsy-confirmed adult NAFLD patients serum levels of the primary methylglyoxal-derived advanced glycated endproduct, hydroimidazolone (MG-H1) were found strongly correlated with body mass index (r=0.619, p<0.0001). Conclusions: We characterize, for the first time, the post-translational modification and regulation of GLO1 expression in response to hepatic lipid loading with functional consequences in NAFLD patients.
2018-02-16 | PXD001442 | Pride
Project description:Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder and affects approximately one third of the general population.Recent studies have shown that long non-coding (lncRNA) plays critical roles in a myriad of biological processes and human diseases,Since the roles of lncRNA in NAFLD remain unknown,they were investigated in the study.Our findings indicate that the expression profiles of lncRNAs has changed in NAFLD as compared with normal liver, and may provide novel insight into the molecular mechanism underlying the disease and potential novel diagnostic or therapeutic targets for NAFLD. Microarray expression profiling of mRNAs and lncRNAs were conducted using RNA extracted from five NAFLD liver tissues and five normal liver samples.
2015-09-08 | E-GEOD-72756 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis, where treatment options are limited. As the liver secrets most of the blood plasma proteins its diseases should affect the plasma proteome. Plasma proteome profiling on 48 patients with cirrhosis or NAFLD with normal glucose tolerance or diabetes, revealed 8 significantly changing (ALDOB, APOM, LGALS3BP, PIGR, VTN, IGHD, FCGBP and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts with a 2.7-fold expression change in NAFLD and 4-fold change in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE to NAFLD and cirrhosis. DPP4 is a known drug target in diabetes. ANPEP and TGFBI are of interest because of their potential role in extracellular matrix remodeling in fibrosis.
| MSV000084333 | MassIVE