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Relevance of low testosterone to non-alcoholic fatty liver disease.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a condition where there is excess accumulation of triglycerides in the liver in the absence of excess alcohol consumption. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD, one of the most common causes of chronic liver disease in Western populations, is the hepatic component of the metabolic syndrome (MetS) and is associated with increased visceral adipose tissue (VAT), insulin resistance, and dyslipidemia. Studies have also shown that testosterone deficiency is associated with increased VAT and insulin resistance in males while hyperandrogenemia has been associated with increased risk of insulin resistance and VAT in females. Thus, the aims of this review are to discuss the available experimental and epidemiological data evaluating the association between testosterone and NAFLD, to discuss the potential clinical relevance of these data, and to identify gaps in the literature.

SUBMITTER: Mody A

PROVIDER: S-EPMC4577238 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Relevance of low testosterone to non-alcoholic fatty liver disease.

Mody Avni A White Donna D Kanwal Fasiha F Garcia Jose M JM

Cardiovascular endocrinology 20150901 3

Non-alcoholic fatty liver disease (NAFLD) is a condition where there is excess accumulation of triglycerides in the liver in the absence of excess alcohol consumption. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD, one of the most common causes of chronic liver disease in Western populations, is the hepatic component of the metabolic syndrome (MetS) and is associated with increased vis ...[more]

PMID: 26405614

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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.

Dataset Information

Relevance of low testosterone to non-alcoholic fatty liver disease.

Publications

Relevance of low testosterone to non-alcoholic fatty liver disease.

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