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Expression of DNA methyltransferase genes in the livers of mice fed a CFD diet. qRT-PCR analysis of Dnmt1 and Dnmt3a mRNA transcripts (a) and Western blot analysis of DNMT1 and DNMT3A proteins (b). The results are presented as the average fold change in the expression of each gene in the livers of mice fed the CFD diet relative to that in control groups, which were assigned a value 1. White bars – control mice, black bars – mice fed the CFD diet. * -Significantly different from the strain-matched control mice (mean ± SD, n = 5, fold change >2.0, p < 0.05)
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Background
Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and Western countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD; nonetheless, the effect of inter-individual differences in the normal liver epigenome with regard to t...
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シトシンは核酸を構成するピリミジン塩基である。哺乳動物の核酸の代謝経路にお
いて、シチジンはウリジンからシチジンデアミナーゼによって生合成されるため、通
常、シトシンは生合成されない。しかし、先天性免疫不全症の患者では、尿中に多量
のシトシンが排泄されることが報告されている。また生体内において、シトシンの 5
位の炭素は、メチル化されることが知られており、体細胞および生殖細胞のがん抑制
遺伝子におけるシトシンのメチル化は、変異を誘発するため、細胞のがん化と関連し
ている。
現在までに、生体試料中のシトシンの測定法として、HPLC、質量分析、表面増強
ラマン散乱、微分パルスボルタンメトリーなどを用いた方法が開発されている。しか
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Citations
... A global loss of DNA methylation at CpG sites is characteristic of replicative senescence. This loss is followed by a focal increase in DNA methylation at certain CpG islands [96,97] Senescence-associated DNA methylation patterns have been shown to alter expression of genes typically involved in hepatic lipid metabolism in mice fed a choline-and folatedeficient diet [98]. Alterations in the methylome profile of hepatocytes could therefore determine the severity of NAFLD. ...
Cellular senescence is a state of irreversible cell cycle arrest with important physiological functions. However, cellular senescence is also a hallmark of ageing and has been associated with several pathological conditions. A wide range of factors including genotoxic stress, mitogens and inflammatory cytokines can induce senescence. Phenotypically, senescent cells are characterized by short telomeres, an enlarged nuclear area and damaged genomic and mitochondrial DNA. Secretion of proinflammatory proteins, also known as senescence-associated secretory phenotype, is a characteristic of senescent cells that is mainly held accountable for their disease-inducing properties.
In the past decade, cellular senescence gained significant interest due to its putative role in the development of Non-Alcoholic Fatty Liver Disease (NAFLD) and the progression towards Non-Alcoholic Steatohepatitis (NASH). Until recently, it was suggested that hepatocyte cellular senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in fatty liver disease. However, recent work in rodents has suggested that senescence may be a causal factor in NAFLD development. Although causality is yet to be established in humans, current evidence suggests that targeting of senescent cells has novel treatment potential for NAFLD
We aim to provide insight in the quality of the evidence supportive of a causal role of cellular senescence in the development of NAFLD in rodents and humans. We will elaborate on key cellular and molecular features of senescence and discuss the efficacy and safety of novel senolytic drugs to treat or even prevent this disease.
... The effect of genetic diversity on patterns of DNA variation has not been assessed in previous arthropod methylation studies. Knowledge of this has come from mammalian studies: in mice, for example, thousands of methylated cytosines (CpGs) have been found to differ between strains [14,15], which was associated with proximity to DNA polymorphisms [14,16]. Inter-individual polymorphism in DNA methylation has also been observed in humans [17,18]. ...
Background
Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna.
Results
Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age.
Conclusions
Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.
... To investigate further the mechanistic role of the NaAsO 2 -induced DNA methylation changes, we conducted a simultaneous analysis of DMRs and DEGs (Tryndyak et al. 2016). By using this approach, we identified 59 genes exhibiting an inverse correlation between gene-specific methylation and gene expression (Supplementary Table 3), including 25 promoter-or first exon/intron DMR-containing genes ( Fig. 2c and Table 1). ...
... Similar findings were reported recently by Barajas-Olmos et al. (2019), who demonstrated that continuous treatment of human immortalized keratinocyte HaCaT cells with 0.1 µM NaAsO 2 resulted in a progressive accumulation of hypermethylated promoters, a hallmark event in carcinogenesis (Schmutte and Jones 1998;Baylin and Ohm 2006). To determine the mechanistic role of the NaAsO 2 -induced DNA methylation changes, we performed a simultaneous analysis of DMRs and DEGs, an approach that allows identifying key treatment-related pathophysiological events (Tryndyak et al. 2016;Barajas-Olmos et al. 2019). In this analysis, we focused on the genes exhibiting an inverse correlation between gene expression and promoter-or first exon/intron cytosine DNA methylation, a fundamental event that regulates gene transcription (Schmutte and Jones 1998;Baylin and Ohm 2006;Anastasiadi et al. 2018). ...
Chronic exposure to inorganic arsenic is associated with a variety of adverse health effects, including lung, bladder, kidney, and liver cancer. Several mechanisms have been proposed for arsenic-induced tumorigenesis; however, insufficient knowledge and many unanswered questions remain to explain the integrated molecular pathogenesis of arsenic carcinogenicity. In the present study, using non-tumorigenic human liver HepaRG cells, we investigated epigenetic alterations upon prolonged exposure to a noncytotoxic concentration of sodium arsenite (NaAsO2). We demonstrate that continuous exposure of HepaRG cells to 1 µM sodium arsenite (NaAsO2) for 14 days resulted in substantial cytosine DNA demethylation and hypermethylation across the genome, among which the claudin 14 (CLDN14) gene was hypermethylated and the most down-regulated gene. Another important finding was a profound loss of histone H3 lysine 36 (H3K36) trimethylation, which was accompanied by increased damage to genomic DNA and an elevated de novo mutation frequency. These results demonstrate that continuous exposure of HepaRG cells to a noncytotoxic concentration of NaAsO2 results in substantial epigenetic abnormalities accompanied by several carcinogenesis-related events, including induction of epithelial-to-mesenchymal transition, damage to DNA, inhibition of DNA repair genes, and induction of de novo mutations. Importantly, this study highlights the intimate mechanistic link and interplay between two fundamental cancer-associated events, epigenetic and genetic alterations, in arsenic-associated carcinogenesis.
... In addition, the relevance of the DNA methylation has been emphasized by a broad range of studies. Epigenome analyses have revealed different methylation patterns in patients with hepatic dysfunctions, with a close dependence of the injury level of the organ [165][166][167], which could be useful to predict the progression of NAFLD. ...
Introduction:
Non-alcoholic fatty liver disease (NAFLD) affects ~25% of world population and cases have increased in recent decades. These anomalies have several etiologies; however, obesity and metabolic dysfunctions are the most relevant causes. Despite being considered a public health problem, no effective therapeutic approach to treat NAFLD is available. For that, a deep understanding of metabolic routes that support hepatic diseases is needed.
Areas covered:
This review covers aspects of the onset of NAFLD. Thereby, biochemistry routes as well as cellular and metabolic effects of the gut microbiota in body's homeostasis and epigenetics are contextualized.
Expert opinion:
Recently, the development of biological sciences has generated innovative knowledge, bringing new insights and perspectives to clarify the systems biology of liver diseases. A detailed comprehension of epigenetics mechanisms will offer possibilities to develop new therapeutic and diagnostic strategies for NAFLD. Different epigenetic processes have been reported that are modulated by the environment such as gut microbiota, suggesting strong interplays between cellular behavior and pathology. Thus, a more complete description of such mechanisms in hepatic diseases will help to clarify how to control the establishment of fatty liver, and precisely describe molecular interplays that potentially control NAFLD.
... In contrast to nutrigenetics studies, nutrigenomics studies provide evidence that diet and/or nutrients have direct impact on gene expression and metabolic pathways involved in obesity and its related metabolic syndromes, leading to differences in health risk [29][30][31][32][33]. For example, diets high in fat and sugar increase the expression of LEP, SREBF1, and PLIN (genes encoding regulators for lipid synthesis and uptake), resulting in an increased risk of obesity [29]. ...
... High saturated fatty acids have also been shown to induce obesity and inflammation through increased expression of proinflammatory cytokines such as TNF and IL6 [30]. Diets deficient in choline and folate have also been associated with increased risk of non-alcoholic fatty liver disease (NAFLD) through the dysregulation of genes involved in lipid metabolism, such as APOE, FOXA1, and PPARGA [31,32]. On the contrary, studies have also suggested that some dietary components have beneficial effects on obesity management through the regulation of gene expression. ...
The increasing prevalence of obesity is becoming a global health concern due to its association with chronic diseases including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular diseases. Obesity occurs when energy intake outweighs energy expenditure, leading to a conventional intervention strategy being “eat less and move more.” However, this strategy does not consider the influence of genetic factors and their interactions with environmental factors (diets and physical activity), making obesity prevention and management inefficient. To better understand obesity, research in nutrigenetics and nutrigenomics seek to explore the influence of genetic variations on dietary responses, and how dietary components alter gene expression in obese individuals. Current evidence suggests that variations in genes involved in lipid regulation, carbohydrate metabolism, and energy homeostasis are strongly associated with the risk of obesity and its related metabolic syndromes. In addition, diet-gene interactions influence intervention effectiveness for obesity management. By examining obesity-related metabolic pathways, we can reveal the functional basis of diet-gene interactions in relation to obesity risk. Although limitations exist within the current literature, emerging evidence indicates that obesity risk and intervention can be affected by diet-gene interactions, and continued research is needed for further exploration.
... Эндогенный синтез ω6 и ω3 ПНЖК осуществляется последовательными стадиями элонгации и десатурации незаменимых жирных кислот и их производных. Незаменимыми, или эссенциальными, жирными кислотами, которые должны быть получены из ежедневного рациона, являются α-линоленовая (18:3ω3) и линолевая (18:2ω6) [29]. Млекопита-ющие не могут синтезировать данные кислоты ввиду отсутствия ферментов, катализирующих введение двойных связей в цепь жирной кислоты далее 9-го углеродного атома [18,30]. ...
Aim. To present literature data on the metabolic and genetic mechanisms of impaired fatty acid (FA) synthesis in the development and progression of non-alcoholic fatty liver disease (NAFLD).
General findings. NAFLD is a widespread disease progressing from steatosis to non-alcoholic steatohepatitis (NASH), increasing the risk of cirrhosis, liver failure and hepatocellular carcinoma. Progression of NAFLD and the development of NASH are closely related to lipid metabolism disorders caused not only by insufficient alimentary intake of fatty acids, but also by a decrease in the efficiency of their endogenous processing. The regulation of fatty acid metabolism involves enzymes desaturase (FADS1, FADS2) and elongase (ELOVL2 and ELOVL5) fatty acids. Desaturases are encoded by the FADS1 and FADS2 genes for fatty acid desaturases. Polymorphisms in the genes of fatty acid desaturases determine the effectiveness of PUFA endogenous processing. Violations in the activity of FADS1 and FADS2 and their genes are accompanied by dysregulation of the metabolic pathway involved in the biosynthesis of fatty acids. This leads to the damage of cell membranes, whose main components are represented by phospholipids. The progression of NAFLD is associated with the powerful toxicity of lipids released in the liver parenchyma upon the loss of the cell biomembrane integrity.
Conclusions. Further research into the NAFLD genetic mechanisms regulating the metabolism of fatty acids appears to be promising for a deeper understanding of the pathogenesis of this multifactorial disease.
... Evidence for this hypothesis was reduced glycogen content in Mtrr gt/gt female livers as determined by PAS stain in combination with a down-regulation of genes involved in glycogen synthesis. Indeed, mice fed a folate-and/or choline-deficient diet exhibit alterations in hepatic DNA methylation of genomic regions that are associated with genes related to carbohydrate metabolism [62]. In another context, folate transporters (e.g., FOLR1) and metabolic enzymes (i.e., MTR and MTHFR) are highly expressed in specialized placental cells involved in glycogen storage and metabolism [63]. ...
Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one‑carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrr
gt
). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrr
gt
mutation in mice was previously shown to disrupt one‑carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrr
gt/gt
female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrr
gt/gt
livers showed evidence of reduced β-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrr
gt/gt
livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrr
gt/gt
livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrr
gt/gt
female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage.
... In recent years, there has been a growing interest in the study of epigenetic mechanisms affecting genes responsible for NAFLD development [72][73][74][75][76]. Tissue-specific epigenetic modifications, associated with the histological severity and prognosis of NAFLD, have been observed in both nuclear [77][78][79][80] and mitochondrial genomes [81]. Whereas alterations in DNA methylation, histone marks, and noncoding RNAs have been extensively investigated in fatty liver [74,75,82], data examining the impact of DNA hydroxymethylation in the initiation and progression of NAFLD remain scarce [49,83,84]. ...
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disorders among adults, children, and adolescents, and a growing epidemic, worldwide. Notwithstanding the known susceptibility factors for NAFLD, i.e., obesity and metabolic syndrome, the exact cause(s) of this disease and the underlying mechanisms of its initiation and progression are not fully elucidated. NAFLD is a multi-faceted disease with metabolic, genetic, epigenetic, and environmental determinants. Accumulating evidence shows that exposure to environmental toxicants contributes to the development of NAFLD by promoting mitochondrial dysfunction and generating reactive oxygen species in the liver. Imbalances in the redox state of the cells are known to cause alterations in the patterns of 5-hydroxymethylcytosine (5hmC), the oxidative product of 5-methylcytosine (5mC), thereby influencing gene regulation. The 5hmC-mediated deregulation of genes involved in hepatic metabolism is an emerging area of research in NAFLD. This review summarizes our current knowledge on the interactive role of xenobiotic exposure and DNA hydroxymethylation in the pathogenesis of fatty liver disease. Increasing the mechanistic knowledge of NAFLD initiation and progression is crucial for the development of new and effective strategies for prevention and treatment of this disease.
... These effects include both therapeutic effects 25 and drug-induced organ injuries, especially hepatotoxicity. 13,14,26,27 In this study, we systematically screened and validated DNA methylation markers associated with the occurrence of ATLI, and the effects of the newly identified markers were verified using a hepatocyte cell model. We have, we believe for the first time, combined whole-genome DNA methylation association analysis with a functional study to investigate the risk factors for ATLI in an attempt to identify reliable biomarkers for predicting and preventing the occurrence of drug-induced liver injury (DILI), which is also crucial for improving TB control. ...
Tuberculosis (TB) is one of the most prevalent infections. However, anti‐TB drugs induce adverse liver injury in up to 40% of patients. Studies on candidate genes have suggested that single‐nucleotide polymorphisms account for only a small contribution to the occurrence of anti‐tuberculosis drug‐induced liver injury (ATLI). In this study, whole‐genome DNA methylation analysis was performed to systematically screen the ATLI‐associated factors in a 49 versus 51 case‐control population. Next, 34 identified candidate probes were validated using MassARRAY in 296 cases and 288 controls. Our results indicated that 12 CpG sites on seven probes were positively associated with ATLI‐risk. Furthermore, we applied a CRISPR/Cas9 mediated methylation modifiable cell model and demonstrated that four CpGs in or near the gene region of AK2, SLC8A2 and PSTPIP2 affected the cellular response to rifampicin treatment. This study provides new biomarkers associated with ATLI occurrence. This article is protected by copyright. All rights reserved.
... To investigate this hypothesis, Tryndyak et al. induced NAFLD via a choline-and folate-deficient diet into two different mouse strains, namely the A/J and WSB/EiJ mice, which are known to have different susceptibility to the development of the disease. Indeed, the more severe steatosis, observed in the WSB/EiJ mice, as compared to the A/J mice, was accompanied by different DNA and histone methylation profiles of NAFLD-related genes and genes related to hepatic lipid accumulation and subsequent alteration in their expression (42). These changes suggest that alterations in the epigenetic profile of hepatocytes could determine the severity of NAFLD. ...
In recent years cellular senescence has generated a lot of interest among researchers due to its involvement in normal aging process and also in common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to Non‐Alcoholic Steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning and liver fibrosis. The development of Non‐Alcoholic Fatty Liver Disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver which may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. In this review we summarize the current literature on the impact of cellular senescence in NAFLD/NASH, and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally we identify the open questions and issues to be addressed in the near future. This article is protected by copyright. All rights reserved.
