Altered DNA Methylation Sites in Peripheral Blood Leukocytes from Patients with Simple Steatosis and Nonalcoholic Steatohepatitis (NASH)

Wu, Jiayu; Zhang, Ruinan; Shen, Feng; Yang, Rui‐Xu; Zhou, Detang; Cao, Hongyan; Chen, Guangyu; Pan, Qin; Fan, Jian‐Gao

doi:10.12659/msm.909747

Cited by 28 publications

(23 citation statements)

References 40 publications

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“…For instance, an enhancer (Chr15:10268884-10281154) with higher H3K27ac enrichment in the control was related to TAOK3 (P-value = 2.9e-2, Cor = 0.86), a gene associated with immune processes (Hammad et al, 2017). In contrast, a region (Chr2: 75160695-75163487) with increased hyper-acetylation in FLHS was identified near ZNF622, consistent with the known role of this gene in hepatic steatosis (Wu et al, 2018b). Together, these results reveal the widespread dysregulation of histone acetylation in the liver of FLHS chickens.…”

Section: Flhs-associated Differential H3k27ac Peaks In the Liversupporting

confidence: 68%

Dysregulated H3K27 Acetylation Is Implicated in Fatty Liver Hemorrhagic Syndrome in Chickens

Zhu

Zeng

et al. 2021

Front. Genet.

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Epigenetic regulation of gene expression has been reported in the pathogenesis of metabolic disorders such as diabetes and liver steatosis in humans. However, the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in chickens have been rarely studied. H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing and high-throughput RNA sequencing was performed to compare genome-wide H3K27ac profiles and transcriptomes of liver tissue between healthy and FLHS chickens. In total, 1,321 differential H3K27ac regions and 443 differentially expressed genes were identified (| log2Fold change| ≥ 1 and P-value ≤ 0.05) between the two groups. Binding motifs for transcription factors involved in immune processes and metabolic homeostasis were enriched among those differential H3K27ac regions. Differential H3K27ac peaks were associated with multiple known FLHS risk genes, involved in lipid and energy metabolism (PCK1, APOA1, ANGPTL4, and FABP1) and the immune system (FGF7, PDGFRA, and KIT). Previous studies and our current results suggested that the high-energy, low-protein (HELP) diet might have an impact on histone modification and chromatin structure, leading to the dysregulation of candidate genes and the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which causes excessive accumulation of fat in the liver tissue and induces the development of FLHS. These findings highlight that epigenetic modifications contribute to the regulation of gene expression and play a central regulatory role in FLHS. The PPAR signaling pathway and other genes implicated in FLHS are of great importance for the development of novel and specific therapies for FLHS-susceptible commercial laying hens.

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Section: Flhs-associated Differential H3k27ac Peaks In the Liversupporting

confidence: 68%

Dysregulated H3K27 Acetylation Is Implicated in Fatty Liver Hemorrhagic Syndrome in Chickens

Zhu

Zeng

et al. 2021

Front. Genet.

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“…( 28 ) Wu et al reported that the DNA methylation levels of CRLS1 in patients with NASH were significantly different from those in patients with fatty liver alone. ( 29 ) Here, we identified that CRLS1 alleviated inflammation by interfering with Ikkβ/NF‐κB signaling. Inflammation is closely related to metabolic disorders such as obesity.…”

Section: Discussionmentioning

confidence: 87%

Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation

Xiong

et al. 2020

Hepatology

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BaCKgRoUND aND aIMS: NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. appRoaCH aND ReSUltS: Here, we discovered that CRLS1 was significantly down-regulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA-mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocytespecific Crls1-knockout (Crls1-HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol diet-induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. CoNClUSIoNS: In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3. (Hepatology 2020;72:1949-1967). N onalcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide and includes simple steatosis, NASH, and liver cirrhosis. (1) NASH usually follows simple hepatic steatosis and is characterized by lipid accumulation, insulin resistance, severe inflammation, and fibrosis in the liver. (2) As an expanding health problem, NASH has been projected to become the primary cause of liver transplantation in the next decade because of its potentially fatal pathology, leading to increased risks of cirrhosis, hepatocellular carcinoma, and liver failure. (3) Although extensive clinical and basic research has been conducted in this field, there are currently no satisfactory effective therapies for NASH. (4,5) Therefore, studying the complicated

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“…Moreover, genome-wide DNA methylation analysis study using peripheral blood leukocytes has identified six differentially methylated CpG sites in patients with NAFLD (simple steatosis and NASH) compared with healthy controls. Serum liver enzymes and plasma cholesterol levels were directly correlated with the level of DNA methylation as well as the presence of simple steatosis or NASH [ 45 ].…”

Section: Role Of Microbiota-derived Metabolite Epigenetic Regulation mentioning

confidence: 99%

Epigenetic Markers and Microbiota/Metabolite-Induced Epigenetic Modifications in the Pathogenesis of Obesity, Metabolic Syndrome, Type 2 Diabetes, and Non-alcoholic Fatty Liver Disease

et al. 2019

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Purpose of Review The metabolic syndrome is a pathological state in which one of the key components is insulin resistance. A wide spectrum of body compartments is involved in its pathophysiology. Genetic and environmental factors such as diet and physical activity are both related to its etiology. Reversible modulation of gene expression without altering the DNA sequence, known as epigenetic modifications, has been shown to drive this complex metabolic cluster of conditions. Here, we aim to examine some of the recent research of specific epigenetically mediated mechanisms and microbiota-induced epigenetic modifications on the development of adipose tissue and obesity, β-cell dysfunction and diabetes, and hepatocytes and non-alcoholic fatty disease. Recent Findings DNA methylation patterns and histone modifications have been identified in this context; the integrated analysis of genome, epigenome, and transcriptome is likely to expand our knowledge of epigenetics in health and disease. Epigenetic modifications induced by diet-related microbiota or metabolites possibly contribute to the insulin-resistant state. Summary The identification of epigenetic signatures on diabetes and obesity may give us the possibility of developing new interventions, prevention measures, and follow-up strategies.

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Altered DNA Methylation Sites in Peripheral Blood Leukocytes from Patients with Simple Steatosis and Nonalcoholic Steatohepatitis (NASH)

Cited by 28 publications

References 40 publications

Dysregulated H3K27 Acetylation Is Implicated in Fatty Liver Hemorrhagic Syndrome in Chickens

Dysregulated H3K27 Acetylation Is Implicated in Fatty Liver Hemorrhagic Syndrome in Chickens

Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation

Epigenetic Markers and Microbiota/Metabolite-Induced Epigenetic Modifications in the Pathogenesis of Obesity, Metabolic Syndrome, Type 2 Diabetes, and Non-alcoholic Fatty Liver Disease

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