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

作者：Gabriella Assante, Sriram Chandrasekaran, Stanley Ng, Aikaterini Tourna, Carolina H. Chung, Kowsar A. Isse, Jasmine L. Banks, Ugo Soffientini, Céline Filippi, Anil Dhawan, Mo Liu, Steve Rozen, Matthew Hoare, Peter J. Campbell, J. William O. Ballard, Nigel Turner, Margaret J. Morris, Shilpa Chokshi, Neil A. Youngson · 发表于：Genome Medicine · 年份：2022 · DOI：10.1186/s13073-022-01071-5 · 被引用次数：42 · 研究领域：Liver Disease Diagnosis and Treatment、Alcohol Consumption and Health Effects、Cancer, Hypoxia, and Metabolism

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 H...