DNA Methylation in Nonalcoholic Fatty Liver Disease
Abstract
:1. Introduction
2. Histological Features of NASH
2.1. Steatosis
2.2. Hepatocyte Ballooning
2.3. Inflammation
2.4. Fibrosis
3. Pathway of DNA Methylation
3.1. DNA Methylation Pathways: DNA Methyltransferases (DNMTs)
3.2. DNA Demethylation Pathways: Ten Eleven Translocation Enzymes (TETs)
4. DNA Methylation in NAFLD
4.1. Animal Models
4.2. Human Studies
4.2.1. Liver Tissue (Hepatic DNA)
4.2.2. Peripheral Blood or Plasma (Leukocyte DNA or Circulating Cell-Free DNA)
4.3. Dysregulation of the DNA Methylation Process
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
NAFLD | Nonalcoholic fatty liver disease |
MetS | Metabolic syndrome |
NASH | Nonalcoholic steatohepatitis |
CpG | Cytosine-phospho-guanine |
HSC | Hepatic stellate cell |
CK8/18 | Cytokeratin 8 and 18 |
IR | Insulin resistance |
MDB | Mallory-Denk body |
5-mC | 5-methylcytosine |
MeCP2 | Methyl CpG binding protein 2 |
MBD | Methyl-CpG-binding domain |
DNMT | DNA methyltransferase |
SAM | S-adenosyl methionine |
5-hmC | 5-hydroxymethylcytosine |
TET | Ten Eleven Translocation |
TG | Triglyceride |
HFD | High-fat diet |
HFS | High-fat and high-sucrose |
HFrD | High-fructose diet |
WD | Western diet |
HCC | Hepatocellular carcinoma |
mtDNA | Mitochondrial DNA |
cfDNA | Cell-free DNA |
T2D | Type 2 diabetes |
HG | High-glucose |
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Gene Name (CpG Site) | Alteration | Sample Type | Correlations with DNA Methylation | Number of Subjects | DNA Methylation Measurement Method(s) | Year [Reference] |
---|---|---|---|---|---|---|
TRIM4 (cg02756107, cg25591451), PRC1 (cg01407062), TUBA1B (cg13709639) | Hypo | PHx specimen | NASH-HCC specific, necroinflammatory grade of NASH, poorer tumor differentiation | 36 controls, 22 NASH-HCC (paired cancerous and non-cancerous tissues), 36 viral-HCC (HBV and/or HCV) | Infinium HumanMethylation450 BeadChip | 2020 [126] |
WHSC1 (cg03150409), MAML3 (cg14497545), WDR6 (cg13003239), FLCN (cg07138452) | WHSC1, MAML3: hypo; WDR6, FLCN: hyper | Liver biopsy or PHx specimen | NASH-HCC specific | 55 controls,113 NASH, 22 NASH-HCC, 37 viral hepatitis or cirrhosis (13 HBV, 23 HCV, 1 both), 37 viral-HCC | Infinium HumanMethylation450 BeadChip | 2017 [125] |
HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC | Hyper | Paraffin-embedded liver biopsy | 8-OHdG | 65 NAFLD | MethyLight assay | 2016 [118] |
FADS2 (cg06781209, cg07999042) | Hypo | Liver biopsy | D6D activity, FADS2 rs174616 1 (cg07999042) | 95 obesity | Infinium HumanMethylation450 BeadChip | 2019 [120] |
BCAT1 (cg09800500, cg07479001, cg16490209) | Hypo | Frozen liver biopsy | Poor outcome 2 | 86 NAFLD 3 (47 mild and 39 advanced fibrosis) | Infinium HumanMethylation450 BeadChip | 2018 [123] |
APO genes, NPC1L1, STARD, GRHL | APO, NPC1L1, STARD: hyper; GRHL: hypo | Liver biopsy | NAFLD, liver fibrosis | 75 controls, 103 NAFLD | Infinium HumanMethylation450 BeadChip | 2017 [122] |
CYP27A1, SLC51A, SLC27A5, SLCO2B1, SLC47A1, UGT and CYP genes | CYP27A1, SLC51A, SLC27A5, SLCO2B1, SLC47A1: hyper; SLCO2B1: hypo | Liver biopsy | NAFLD, liver fibrosis | 75 controls, 103 NAFLD | Infinium HumanMethylation450 BeadChip | 2016 [121] |
FGFR2 (cg01385327), CASP1 (cg13802966), MAT1A (cg19423196) | FGFR2, CASP1: hypo; MAT1A: hyper | Frozen liver biopsy | Liver fibrosis | 25 controls, 90 NAFLD (52 mild and 38 severe fibrosis) | Infinium HumanMethylation450 BeadChip, bisulfite pyrosequencing | 2013 [114] |
30 CpG sites 4 including LDHB (cg04949489) and SQSTM1 (cg08836954) | N/A | Liver biopsy | NASH, serum fasting insulin level | 95 obesity (34 normal, 35 SS and 26 NASH) | Infinium HumanMethylation450 BeadChip | 2017 [113] |
PC (cg04174538), ACLY (cg25687894), PLCG1 (cg18347630), IGF1 (cg08806558), IGFBP2 (cg11669516), PRKCE (cg04035064), GALNTL4 (cg16337763), GRID1 (cg27317356), IP6K3 (cg10714061) | PC, IGF1, IGFBP2, GRID1: hyper; ACLY, PLCG1, PRKCE, GALNTL4, IP6K3: hypo | Frozen liver biopsy | NAFLD | 18 controls, 45 obesity (18 healthy obese, 12 SS and 15 NASH; including 23 post-bariatric patients) | Infinium HumanMethylation450 BeadChip, bisulfite sequencing | 2013 [31] |
Global DNA methylation | Hypo | Liver biopsy | Inflammation, liver fibrosis, disease progression, serum homocysteine level | 18 controls, 47 NAFLD | MethylFlash Methylated DNA Quantification Kit 5 | 2020 [124] |
PPARα, PPARγ, TGFβ1, PDGFα | PPARα, PPARγ: hyper; TGFβ1, PDGFα: hypo | Paraffin-embedded liver biopsy | Liver fibrosis | 17 NAFLD (8 mild and 9 severe fibrosis) | Bisulfite pyrosequencing | 2015 [30] |
MT-ND6 | Hyper | Liver biopsy | NAS, liver fibrosis | 18 controls, 45 NAFLD (23 SS and 22 NASH) | MS-PCR | 2013 [116] |
PPARGC1A | Hyper | Liver biopsy | Plasma fasting insulin level, HOMA-IR | 11 controls, 63 NAFLD | MS-PCR | 2010 [115] |
DPP4 | Hypo | Frozen liver biopsy | Hepatic steatosis | 96 obesity | Bisulfite pyrosequencing | 2017 [98] |
Gene Name (CpG Site) | Alteration | Sample Type | Correlations with DNA Methylation | Number of Subjects | DNA Methylation Measurement Method(s) | Year [Reference] |
---|---|---|---|---|---|---|
152 CGIs | 120 CGIs: hyper; 32 CGIs: hypo | Peripheral blood | Age acceleration, liver fibrosis | 18 controls, 44 NASH (15 F2 and 29 F3) | Infinium HumanMethylation450 BeadChip | 2018 [147] |
22 CpG sites including LINC00649 (cg08309687) | 17 genes including LINC00649: hypo; 5 genes: hyper | Peripheral blood | Hepatic fat, risk for NAFLD and new-onset T2D (cg08309687) | 3400 EA, 401 HA, 724 AA | Infinium HumanMethylation450 BeadChip | 2019 [140] |
ACSL4 (cg15536552), CRLS1 (cg05131957), CPT1A (cg00574958), SIGIRR (cg13463639), SSBP1 (cg12473838), ZNF622 (cg16398128) | ACSL4: Hypo 1 | Peripheral blood | NASH | 30 controls, 35 NAFLD (18 SS and 17 NASH) | Infinium HumanMethylation450 BeadChip, bisulfite pyrosequencing | 2018 [139] |
ACSL4 (cg15536552), CPT1C (cg21604803) | Hypo 2 | Risk for NAFLD, susceptibility to NASH (cg15536552) | 2018 [138] | |||
SLC7A11(cg06690548) | Hypo | Peripheral blood | Hepatic steatosis, serum liver enzymes (GGT, ALT) | 1450 participants (731 from discovery cohort, 719 from replication cohort) | Infinium HumanMethylation450 BeadChip | 2017 [137] |
PPARγ | Hyper 3 | Plasma | Liver fibrosis | 9 controls, 26 NAFLD (14 mild and 12 severe fibrosis), 13 ALD cirrhosis | Bisulfite pyrosequencing | 2017 [136] |
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Hyun, J.; Jung, Y. DNA Methylation in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2020, 21, 8138. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218138
Hyun J, Jung Y. DNA Methylation in Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences. 2020; 21(21):8138. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218138
Chicago/Turabian StyleHyun, Jeongeun, and Youngmi Jung. 2020. "DNA Methylation in Nonalcoholic Fatty Liver Disease" International Journal of Molecular Sciences 21, no. 21: 8138. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218138