Trends in Genetics
ReviewThe Epigenetic Drug Discovery Landscape for Metabolic-associated Fatty Liver Disease
Section snippets
Metabolic-associated Fatty Liver Disease: A Complex Pathogenesis
MAFLD (see Glossary), formerly named nonalcoholic fatty liver disease (NAFLD), is the most common liver disease and affects ~25–30% of the global population. Its incidence and prevalence have risen in parallel with the epidemics of obesity and type 2 diabetes mellitus (T2DM) [1,2]. Modelling studies suggest that the prevalence of MAFLD and consequent advanced fibrosis and hepatocellular cancer (HCC) will continue to rise globally for at least another decade [3]. Notably, MAFLD is part of a
Epigenetics: Gene–Environment Interactions
The human epigenome provides an important clue for understanding the basis of gene–environment interactions, because it exhibits high plasticity in adaptation to environmental cues, such as diet, toxins, and stress, over the life span to modulate gene expression and functional states of the body, via the phenomenon of de novo epigenetic writing (Figure 1). A twin study demonstrated that, although monozygotic twins have almost identical genomes and similar epigenomes in early life, their
Epigenetic Changes in MAFLD at Cell Type-specific Level
MAFLD is characterised by substantial clinical heterogeneity and, at cellular levels, the liver is composed of heterogeneous cell populations that all likely contribute to this overall variation. Hence, deciphering heterogeneity at a cellular level is pivotal to clarify the intrapatient variations that are observed. Epigenetic changes exhibit marked cell-dependent patterns; changes in the key cells implicated in MAFLD pathogenesis, namely hepatocytes, hepatic stellate cells, and liver
The Interplay between Metabolism and Epigenetics Is Dysregulated in MAFLD
Accumulating evidence supports a role for crosstalk between metabolism and epigenetics. As discussed earlier, fine-tuned interactions between various epigenetic modifiers regulate various metabolic pathways. Conversely, metabolic reprogramming can directly influence the epigenome landscape through at least one of three major mechanisms: (i) altering the cellular concentration of specific metabolites that regulate the activities of chromatin-modifying enzymes via acting as epigenetic cofactors
Translational Implications
Clarifying the epigenetic basis of MAFLD has not only deepened our understanding of the disease development, but also has translational implications as discussed herein.
Concluding Remarks
Although epigenetics therapy appears promising, there is a multitude of challenges that will delay their development. First, epigenetic heterogeneity and the dynamic nature of epigenetic marks is a double-edged sword. Although reversibility renders epigenetics as an attractive target, this dynamic and the fact that epigenetic changes are both tissue and context specific are a major challenge. Another concern about epigenetic therapy is that it is highly nonspecific and induce shot-gun global
Acknowledgements
M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; and a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422). H.G. has received funding from the NOVO Nordisk Foundation.
Glossary
- Epigenetics therapy
- use of drugs or other epigenome-editing tools, such as CRISPR, to modify epigenetic control of gene expression for therapeutic purposes.
- Hepatic stellate cells (HSCs)
- represent ∼10% of all resident liver cells and are interposed between hepatocytes and liver sinusoidal endothelial cells. They are the main storage site for retinoids (vitamin A and metabolites), contained within lipid droplets. There is unequivocal evidence that activation of HSCs is the central driver of
References (121)
Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030
J. Hepatol.
(2018)- et al.
NAFLD: a multisystem disease
J. Hepatol.
(2015) Genetics and epigenetics of NAFLD and NASH: Clinical impact
J. Hepatol.
(2018)In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model
Am. J. Obstet. Gynecol.
(2014)Infant nutrition and maternal obesity influence the risk of non-alcoholic fatty liver disease in adolescents
J. Hepatol.
(2017)Longer lactation duration is associated with decreased prevalence of non-alcoholic fatty liver disease in women
J. Hepatol.
(2019)Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease
J. Hepatol.
(2015)Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet
J. Hepatol.
(2009)Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation
J. Hepatol.
(2013)PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis
J. Hepatol.
(2017)
miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting
Cell Metab.
miRNAs in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis
J. Hepatol.
miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease
J. Hepatol.
A polymorphism in the Irisin-encoding gene (FNDC5) associates with hepatic steatosis by differential miRNA binding to the 3'UTR
J. Hepatol.
FibroGENE: a gene-based model for staging liver fibrosis
J. Hepatol.
Nuclear long noncoding RNAs: key regulators of gene expression
Trends Genet.
Urea cycle dysregulation in non-alcoholic fatty liver disease
J. Hepatol.
Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension
J. Hepatol.
Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway
Hepatobiliary Pancreat. Dis. Int.
miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression
J. Hepatol.
miR-133a mediates TGF-beta-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis
J. Hepatol.
miR-185 inhibits fibrogenic activation of hepatic stellate cells and prevents liver fibrosis
Mol. Ther. Nucleic Acids
miR-455-3p alleviates hepatic stellate cell activation and liver fibrosis by suppressing HSF1 expression
Mol. Ther. Nucleic Acids
TUG1 is involved in liver fibrosis and activation of HSCs by regulating miR-29b
Biochem. Biophys. Res. Commun.
The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways
Nat. Commun.
A novel mammalian flavin-dependent histone demethylase
J. Biol. Chem.
S-adenosyl-L-methionine analogs as enhanced methyl donors: towards novel epigenetic regulators
Chem. Phys. Lett.
Acetyl-CoA carboxylase regulates global histone acetylation
J. Biol. Chem.
Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes
Mol. Cell
DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery
Cell Metab.
A proof-of-concept for epigenetic therapy of tissue fibrosis: inhibition of liver fibrosis progression by 3-deazaneplanocin A
Mol. Ther.
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
Nat. Rev. Gastroenterol. Hepatol.
MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease
Gastroenterology
Lean NAFLD: A distinct entity shaped by differential metabolic adaptation
Hepatology
Genetic and epigenetic mechanisms of NASH
Hepatol. Int.
Metabolic syndrome and severity of fibrosis in nonalcoholic fatty liver disease: An age-dependent risk profiling study
Liver Int.
Epigenetic differences arise during the lifetime of monozygotic twins
Proc. Natl. Acad. Sci. U. S. A.
Meta-analysis of the heritability of human traits based on fifty years of twin studies
Nat. Genet.
Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease
J. Clin. Invest.
A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates
FASEB J.
Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations
Genome Biol.
Exercise prevents maternal high-fat diet-induced hypermethylation of the Pgc-1a gene and age-dependent metabolic dysfunction in the offspring
Diabetes
Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice
Proc. Natl. Acad. Sci. U. S. A.
Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns
Obesity
Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter
Hepatology
Epigenetics and epigenomics in diabetic kidney disease and metabolic memory
Nat. Rev. Nephrol.
Liver DNA methylation of FADS2 associates with FADS2 genotype
Clin. Epigenetics
The role of diet and exercise in the transgenerational epigenetic landscape of T2DM
Nat. Rev. Endocrinol.
Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control
Nat. Commun.
Epigenetics in liver disease
Hepatology
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A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression
2023, Pathology Research and PracticeMetabolic dysfunction: The silenced connection with fatty liver disease
2023, Annals of HepatologyLoss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming
2023, Metabolism: Clinical and ExperimentalAssociation of genetic and epigenetic changes of insulin like growth factor binding protein-1 in Egyptian patients with type 2 diabetes mellitus
2023, Diabetes Research and Clinical PracticeRPA1 controls chromatin architecture and maintains lipid metabolic homeostasis
2022, Cell ReportsCitation Excerpt :The pathogenic mechanisms of hepatic steatosis are complex and multifactorial, including diet, environmental factors, intestinal microbiota, and genetic and epigenetic (refers to both heritable changes in gene expression and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable) factors (including DNA methylation, histone modifications, chromatin remodeling, and regulation by non-coding RNA) (Diehl and Day, 2017). Epigenetic dysregulation, including transcriptional control, chromatin remodeling, and histone modifications, is predicted to be a major determinant of NAFLD (Bayoumi et al., 2020; Eslam et al., 2018). Thus, identifying epigenetic regulators of NAFLD would provide insights into the pathogenesis of this disease and lead to therapeutic options for treatment of NAFLD.