Trends in Genetics
Volume 36, Issue 6, June 2020, Pages 429-441
Journal home page for Trends in Genetics

Review
The Epigenetic Drug Discovery Landscape for Metabolic-associated Fatty Liver Disease

https://doi.org/10.1016/j.tig.2020.03.003Get rights and content

Highlights

  • MAFLD is the most prevalent liver disease and affects a quarter of the global population, with serious hepatic and extrahepatic consequences. The spectrum of MAFLD extends from hepatic fat accumulation to inflammation and, in some cases, to liver fibrosis and cancer.

  • Human and animal studies indicate that MAFLD is associated with widescale alterations in the epigenetic landscape during its development and progression.

  • Epigenetics-based drugs and editing tools are emerging as a promising therapeutic option to restore the normal (healthy) epigenetic landscape. This field has been enabled by the development of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology for locus-specific epigenetic targeting.

Despite decades of research, effective therapies for metabolic (dysfunction)-associated fatty liver disease (MAFLD) are lacking. An increasing body of evidence suggests that epigenetic dysregulation is frequent in MAFLD, and orchestrates many aspects of its development and progression. Furthermore, the high plasticity of epigenetic modifications in response to environmental cues renders epigenetics a novel area for therapeutic drug discovery. Over recent years, several epigenetics-based drugs and diagnostic biomarkers have entered clinical development and/or obtained regulatory approval. Here, we review recent advances in our understanding of epigenetic regulation and programming during MAFLD, including DNA methylation, histone modifications, chromatin remodelling, transcriptional control, and noncoding (nc)RNAs. We also discuss the potential translational implications and challenges of epigenetics in the context of MAFLD.

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

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