Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease
Abstract
:1. Introduction
2. Epigenetic Mechanisms Underlying the Link between Nutrition and Aberrant Gene Expression in NAFLD
2.1. DNA Methylation and NAFLD
2.2. Histone Post-Translational Modifications in NAFLD
3. Epigenetic Studies’ Limitations
4. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Arnlt | Aryl hydrocarbon receptor nuclear translocator-like |
CpG | Cytosine-phospho-guanine |
CXCL5 | C-X-C Motif Chemokine Ligand 5 |
DNMT | DNA methyltransferase |
HATs | Histone acetyltransferases |
HCC | Hepatocellular carcinoma |
HDACis | Histone deacetylase inhibitors |
HDACs | Histone deacetylases |
HDMs | Histone demethylases |
HFD | High-fat diet |
HMTs | Histone methyltransferases |
HSC | Hepatic stellate cell |
IR | Insulin resistance |
MetS | Metabolic syndrome |
mTOR | mammalian target of rapamycin |
NAFLD | Nonalcoholic fatty liver disease |
NASH | Nonalcoholic steatohepatitis |
PPARγ | Peroxisome proliferator-activated receptor γ |
PTEN | Phosphatase and tensin homolog |
S6K1 | Ribosomal protein S6 kinase beta-1 |
SAM | S-adenosyl methionine |
Sirt1 | Sirtuin 1 |
STAT5 | Signal transducer and activator of transcription 5 |
T2DM Type 2 | diabetes mellitus |
TG | Triglyceride |
UPS10 | Ubiquitin-Specific Protease 10 |
α-SMA | Alpha Smooth Muscle Actin |
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Gene | Stage | Associated Disease Mechanisms | References |
---|---|---|---|
Srebf2 | Hepatic steatosis | Supplementation with methyl donors containing folic acid, choline, betaine, and Vitamin B12 improved liver steatosis by reversing the methylation status in the promoter region of sterol regulatory element binding transcription factor 2 (Srebf2) | [68,73] |
Mttp | Hepatic steatosis | Betaine supplementation decreased DNA methylation of the microsomal triglyceride transfer protein (Mttp) gene promoter in mice and improved HFD-induced hepatic steatosis | [75] |
Pparγ | NAFLD | HFD and palmitic acid alter Pparγ promoter DNA methylation leading to a significant induction of PPARγ expression and enhanced fat accumulation in mice liver, which may lead to NAFLD | [38] |
Nrf2 | NAFLD | Treatment of HepG2 cells with high glucose enhanced methylation level of the Nrf2 promoter whereas Resveratrol reversed the effect, which led to a reduction in TG levels and the expression of lipogenesis-related genes | [78] |
Gnmt | HCC | Reduced Gnmt expression caused by promoter cytosine DNA hypermethylation is one of the key molecular events in the development of NAFLD-derived HCC | [80] |
Pparγ | NAFLD | Hypermethylation at the Pparγ promoter of plasma DNA correlated with with fibrosis severity in patients with NAFLD | [89] |
PGC1-α | NAFLD | Hepatic DNA methylation of of PPARγ coactivator 1- α (PGC1-α) promoter significantly correlates with peripheral insulin resistance and is associated with decreased PGC1-α mRNA expression | [85] |
Pparα, Pparγ, TGFβ1, Collagen 1A1,PDGFα | NAFLDfibrosis | DNA methylation at specific CpGs within PPARα, PPARγ, TGFβ1, Collagen 1A1, and PDGFα genes can distinguish mild from severe fibrosis in NAFLD patients | [83] |
IGFBP2 | NASH | The IGFBP2 (insulin-like growth factor binding protein 2) locuswas hypermethylated and its mRNA downregulated in NASH | [82] |
MT-ND6 | NAFLD | Hepatic methylation and transcriptional activity of the MT-ND6 gene are significantly associated with the histological severity of NAFLD | [86] |
Sirt1, Pparγ | NAFLD | Suv39h2 is significantly elevated in diet-induced obese mice and NAFLD patients, and it increases the methylation levels at histone H3 lysine 9 of both Sirt1 and Pparγ to suppress the gene expression | [94] |
Gene | Stage | Association between Epigenetic Determinant and Gene Expression | References |
---|---|---|---|
SREBP1c, FASN ACLYS, Pparγ | NAFLD | Blocking the hyperacetylation of lysine 9 and 36 at histone 3 (H3K9 and H3K36) in the promoter of lipogenesis-related genes (SREBP1c, FASN, ACLYS, Pparγ) prevented NAFLD | [100] |
Pparα | NAFLDSteatosis | Hepatic lipid accumulation induced aberrant H3K9me3 and H3K4me3 status in Pparα gene and other hepatic lipid catabolism network genes, which may contribute to hepatic steatosis and the pathogenesis of NAFLD | [102] |
ChREBP | Hepatic Steatosis | p300 associates and regulates carbohydrate-responsive element–binding protein (ChREBP) transcriptional activity by acetylation. Inhibition of hepatic p300 activity may be beneficial for treating hepatic steatosis | [103] |
Pparγ2 | Hepatic steatosis | Histone H3 lysine 4 (H3K4) methyltransferase MLL4/KMT2D directs overnutrition-induced murine steatosis via its coactivator function for PPARγ2 | [104] |
Pparγ2, CD36, FABP4, PLIN2, CIDEC, | Hepatic steatosis | Overexpressing JMJD2B upregulated Pparγ2 expression which lead to a concomitant increase in its steatosis target genes by removing repressive histone marks H3K9me2 and H3K9me3 near LXREs of lipogenic gene promoters leading to the development of NAFLD | [105] |
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Zaiou, M.; Amrani, R.; Rihn, B.; Hajri, T. Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Biomedicines 2021, 9, 1256. https://doi.org/10.3390/biomedicines9091256
Zaiou M, Amrani R, Rihn B, Hajri T. Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Biomedicines. 2021; 9(9):1256. https://doi.org/10.3390/biomedicines9091256
Chicago/Turabian StyleZaiou, Mohamed, Rim Amrani, Bertrand Rihn, and Tahar Hajri. 2021. "Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease" Biomedicines 9, no. 9: 1256. https://doi.org/10.3390/biomedicines9091256