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Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle.

ABSTRACT: BACKGROUND:Molecular signaling events associated with the necroinflammatory changes in nonalcoholic steatohepatitis (NASH) are not well understood. AIMS:To understand the molecular basis of NASH, we evaluated reversible phosphorylation events in hepatic tissue derived from Class III obese subjects by phosphoproteomic means with the aim of highlighting key regulatory pathways that distinguish NASH from non-alcoholic fatty liver disease (also known as simple steatosis; SS). MATERIALS & METHODS:Class III obese subjects undergoing bariatric surgery underwent liver biopsy (eight normal patients, eight with simple steatosis, and eight NASH patients). Our strategy was unbiased, comparing global differences in liver protein reversible phosphorylation events across the 24 subjects. RESULTS:Of the 3078 phosphorylation sites assigned (2465 phosphoserine, 445 phosphothreonine, 165 phosphotyrosine), 53 were altered by a factor of 2 among cohorts, and of those, 12 were significantly increased or decreased by ANOVA (P < 0.05). DISCUSSION:Statistical analyses of canonical signaling pathways identified carbohydrate metabolism and RNA post-transcriptional modification among the most over-represented networks. CONCLUSION:Collectively, these results raise the possibility of abnormalities in carbohydrate metabolism as an important trigger for the development of NASH, in parallel with already established abnormalities in lipid metabolism.

SUBMITTER: Wattacheril J

PROVIDER: S-EPMC5583035 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle.

Wattacheril Julia J Rose Kristie L KL Hill Salisha S Lanciault Christian C Murray Clark R CR Washington Kay K Williams Brandon B English Wayne W Spann Matthew M Clements Ronald R Abumrad Naji N Flynn Charles Robb CR

Hepatology research : the official journal of the Japan Society of Hepatology 20170419 13

<h4>Background</h4>Molecular signaling events associated with the necroinflammatory changes in nonalcoholic steatohepatitis (NASH) are not well understood.<h4>Aims</h4>To understand the molecular basis of NASH, we evaluated reversible phosphorylation events in hepatic tissue derived from Class III obese subjects by phosphoproteomic means with the aim of highlighting key regulatory pathways that distinguish NASH from non-alcoholic fatty liver disease (also known as simple steatosis; SS).<h4>Mater ...[more]

PMID: 28258704

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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.

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Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle.

Publications

Non-alcoholic fatty liver disease phosphoproteomics: A functional piece of the precision puzzle.

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