Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Abstract

Background The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Methods Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. Results Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. Conclusions Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.

Gene-signatures for early detection of cancers

“…Cluster-1, the gene-set was found to be expressed in Liver, and found to be related with HDL, Amyloid protein and hemolytic anemia. It was also found to be linked with metabolism of Folate & Vita-12 [8, 9, 10] (Figure 6).…”

Epigenetic modifications in obesity‐associated diseases

“…In steatotic hepatocytes, hyperacetylation of genome-wide histones could initiate carcinogenesis by damaging DNA. 101 Recent studies have found that the concurrent activation of acetylated and trimethylated H3K9 in mice can lead to NASH-related HCC, and deacetylation of H4K16 promotes cancer progress by silencing genes associated with cell death. 102,103 In addition to these findings, histone modifications caused by the interactions between a HFD and intestinal microbiome are significant during gastrointestinal tumor development.…”

“…Chromatin becomes slack due to histone acetylation, thereby increasing DNA accessibility and promoting transcriptional activity. In steatotic hepatocytes, hyperacetylation of genome‐wide histones could initiate carcinogenesis by damaging DNA 101 . Recent studies have found that the concurrent activation of acetylated and trimethylated H3K9 in mice can lead to NASH‐related HCC, and deacetylation of H4K16 promotes cancer progress by silencing genes associated with cell death 102,103 .…”

Unravelling the Complex Relationship between Diet and Nephrolithiasis: The Role of Nutrigenomics and Nutrigenetics

“…The exact mechanisms by which fructose modifies urine composition are still not completely understood and a specific epigenetic mechanism exerted by fructose in nephrolithiasis or risk factors for kidney stone formation have not been described. However, from available data, we know that fructose acts via epigenetic mechanisms (ncRNA and DNA methylation) in other conditions [ 57 , 58 , 59 ], such as nonalcoholic fatty liver disease (NAFLD) [ 60 , 61 , 62 ]. Therefore, we can speculate that fructose might act via epigenetic mechanisms to regulate the expression of genes that encode crucial transporters of anti- and prolithogenic urinary molecules.…”