Metabolomics Workbench ST000665 - GNPS - Nonalcoholic fatty liver disease (NAFLD) Studies
Ontology highlight
ABSTRACT:
INSTRUMENT(S): QTOF - NEGATIVE, QTOF - POSITIVE
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Maureen Kachman
PROVIDER: MSV000082692 | GNPS | Thu Aug 02 17:06:00 BST 2018
REPOSITORIES: GNPS
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Project description:Determine the genetic mechanism of action by which variants near PNPLA3 and LYPLAL1 exert their effects on promoting NAFLD
2017-06-05 | ST000665 | MetabolomicsWorkbench
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:Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ~25% worldwide, with significant public health consequences, yet few effective treatments. Human genetics can help elucidate novel biology and identify targets of new therapeutics. Genetic variants in mitochondrial amidoxime reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality, however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalization and mendelian randomization were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra GAN-diet NASH mouse model treated with hepatocyte specific GalNAc-siRNA to understand the in vivo impacts of MTARC1. Results: We show that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids and body composition and these associations are due to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian Randomization, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion and in vivo GalNAc-siRNA mediated knockdown of mARC1 lowered hepatic, but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD.
2023-02-20 | GSE225616 | GEO
Project description:Background and Aims Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ~25% worldwide, with significant public health consequences yet has few effective treatments. Human genetics can help elucidate novel biology and identify targets of new therapeutics. Genetic variants in mitochondrial amidoxime reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality, however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods Analyses including multi-trait colocalization and Mendelian randomization were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra GAN diet NASH mouse model treated with hepatocyte specific GalNAc-siRNA to understand the in vivo impacts of MTARC1. Results We show that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids and body composition and these associations are due to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian Randomization, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion and in vivo GalNAc-siRNA mediated knockdown of mARC1 lowered hepatic, but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD.
2023-04-01 | GSE223652 | GEO
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:Nonalcoholic fatty liver disease represents a spectrum of pathology that ranges from benign steatosis to potentially-progressive steatohepatitis and affects more than 30% of US adults. Advanced NAFLD is associated with increased morbidity and mortality from cirrhosis, primary liver cancer, cardiovascular disease and extrahepatic cancers. Accurate identification of patients at risk for advanced NAFLD is challenging. The aims of this study were to define the liver gene expression patterns that distinguish mild from advanced NAFLD and to develop a gene expression profile associated with advanced NAFLD. We analyzed total RNA from 72 patients with NAFLD (40 with mild NAFLD, fibrosis stage 0-1 and 32 with advanced NAFLD, fibrosis stage 3-4) and developed a gene profile associated with advanced NAFLD. This dataset is part of the TransQST collection.
2013-08-30 | E-GEOD-49541 | biostudies-arrayexpress
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most prevalent hepatic pathology worldwide. However, the precise molecular mechanisms for NAFLD are still not sufficiently explained. Recently, a new mode of cell death (cuproptosis) is found. However, the relationship between NAFLD and cuproptosis remains unclear. We analyzed three public datasets to identify cuproptosis-related genes stably expressed in NAFLD. Then, we performed a series of bioinformatics analyses to explore the relationship between NAFLD and cuproptosis-related genes. Finally, 3 normal control mouse and 3 high-fat diet (HFD)-induced NAFLD C57BL/6J mouse models were established to carry out transcriptome analysis.
2023-04-30 | E-MTAB-11980 | biostudies-arrayexpress
Project description:The aim of this study was to explore the possible action mechanism of fenofibrate in treating non-alcoholic fatty liver disease (NAFLD) through bioinformatic analysis. Statistical and bioinformatic analyses were conducted through Gene Ontology, Gene Set Enrichment Analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG). The control, high-fat diet (HFD), and HFD + fenofibrate (HFD + Fen) groups were analyzed for differentially expressed genes (DEGs). In the HFD versus control dataset analysis, 493 DEGs were identified, of which 200 were upregulated and 293 were downregulated. In the HFD + Fen versus HFD dataset, 449 DEGs, comprising 376 upregulated and 73 downregulated genes, were observed. Two KEGG pathways and one key gene were identified. The key gene mup family appeared to mediate the mechanism underlying NAFLD. Treatment of NAFLD with fenofibrate may occur through the core gene mup.
2023-05-01 | GSE205021 | GEO
Project description:The aim of this sudy is to investigate the prevalence of colorectal cancer (CRC) in patients with nonalcoholic fatty liver disease (NAFLD) and evaluate whether NAFLD is a risk factor for CRC.
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2023-02-27 | GSE225740 | GEO