Revealing the Hidden Code: The Fascinating Link Between Epigenetics & Liver Disease

The landscape of modern medicine has been dramatically reshaped by the emerging field of epigenetics, which investigates the heritable changes in gene expression that occur without any alterations to the underlying DNA sequence. One area where epigenetics has revealed its profound impact is in liver disease research. The liver, a vital organ responsible for numerous metabolic functions, is susceptible to various diseases. Scientists have now begun to uncover how epigenetic modifications play a pivotal role in the development and progression of liver diseases.

 

Epigenetic Alterations in Liver Disease:

 

Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, play pivotal roles in maintaining cellular identity and function. In the context of liver disease, these epigenetic changes can disrupt the finely tuned gene expression patterns, leading to aberrant cellular behavior. Research in recent years has unveiled an intricate connection between epigenetic modifications and liver diseases highlighting the role epigenetic dysregulation plays in the pathogenesis of conditions such as non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD).

 

1. DNA Methylation in Liver Disease:

 

DNA methylation, a well-studied epigenetic mechanism, plays a crucial role in gene regulation by adding a methyl group to the cytosine base of DNA, often leading to gene silencing. In the context of liver disease, aberrant DNA methylation patterns have been observed in key genes involved in cell cycle control, apoptosis, and metabolism.

 

For instance, in patients with non-alcoholic fatty liver disease (NAFLD), there is a notable hypermethylation or abnormal increase in methylation of the peroxisome proliferator-activated receptor alpha (PPARα) gene [1]. This hypermethylation leads to the silencing of PPARα and subsequently reduces its expression. PPARα is responsible for regulating lipid metabolism in the liver but its action is not isolated. Interestingly, some attempts to mitigate the disease through the addition of a PPARα agonist proved ineffective, while other clinical studies are still under investigation [1]. However, this finding uncovered a new therapeutic target—PPARα’s regulation of other epigenetic enzymes (DNMT1, JMJD3, TET, and SIRT1) [1].

 

Conversely, hypomethylation, or abnormal decrease in methylation, has also been implicated in liver disease. The hypomethylation of two genes, Fatty Acid Synthase (FASN) and Stearoyl-CoA Desaturase-1 (SCD1), leads to an increased expression of the respective enzymes they encode. This heightened expression results in the excessive synthesis and accumulation of fatty acids in the liver [2].

 

   2. Histone Modification

 

Histone modifications, comprising acetylation, methylation, phosphorylation, and more, influence the chromatin structure and accessibility of genes. In NASH development, the loss of Sirt3 disrupts mitochondrial protein acetylation, leading to impaired energy production and oxidative stress [3,4]. This imbalance contributes to insulin resistance, dyslipidemia, and hepatic lipid accumulation—hallmarks of metabolic syndrome and NASH. Targeting the Sirt3-mitochondrial acetylation pathway offers potential therapeutic interventions for these disorders.

 

    3. Non-coding RNAs

 

MicroRNAs (miRNAs), a type of non-coding RNAs, have emerged as crucial players in the pathogenesis of non-alcoholic steatohepatitis (NASH), displaying a distinctly different serum circulating miRNA expression profile when compared with non-alcoholic fatty liver (NAFL) [5]. These small non-coding RNA molecules function as post-transcriptional regulators, influencing the expression of multiple genes involved in lipid metabolism, inflammation, and fibrosis. In NASH, specific miRNAs are either upregulated or downregulated, reflecting the dynamic changes occurring during disease progression. The altered miRNA expression in the serum serves as a promising biomarker for distinguishing NASH from NAFL, offering valuable diagnostic and prognostic information. Furthermore, deciphering the functional roles of these dysregulated miRNAs in NASH pathogenesis presents exciting possibilities for targeted therapeutic interventions, aiming to modulate aberrant miRNA expression and potentially ameliorate the severity and progression of NASH.

 

The discovery of epigenetic regulators has opened up new avenues for liver disease treatment, as targeting specific epigenetic marks involved in disease progression holds promise for developing more precise and personalized therapies. Small molecule inhibitors and epigenetic editing tools, such as CRISPR-based approaches, are being explored to modify epigenetic states and restore normal gene expression in diseased liver cells. Moreover, epigenetics has emerged as a key player in the development of biomarkers for both disease diagnosis and disease stage. 

 

Epigenetics has emerged as a pivotal player in shaping the landscape of liver disease research. Unraveling the complex web of epigenetic modifications and their influence on gene expression provides new insights into disease mechanisms and potential therapeutic targets. By harnessing the power of epigenetics, scientists are poised to unlock groundbreaking discoveries that could revolutionize the prevention and treatment of liver diseases, ultimately improving the lives of millions worldwide. As this dynamic field continues to evolve, it offers an exciting future where personalized medicine and precision therapeutics may become a reality for liver disease patients.

 

Written by Christine Mowad & AGED Diagnostics.

 

References

 

1. Theys, C., Lauwers, D., Perez-Novo, C., & Vanden Berghe, W. (2022). PPARα in the Epigenetic Driver Seat of NAFLD: New Therapeutic Opportunities for Epigenetic Drugs?. Biomedicines, 10(12), 3041. https://doi.org/10.3390/biomedicines10123041

2. Wu, J., & Liu, Y. (2021). Evaluation for CpG island methylation of FASN and SREBP promoter in Mongolian gerbil NAFLD model. Archives of Medical Science.

3. Lee, J. H., Friso, S., & Choi, S. W. (2014). Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients, 6(8), 3303–3325. https://doi.org/10.3390/nu6083303

4. Hirschey, M. D., Shimazu, T., Jing, E., Grueter, C. A., Collins, A. M., Aouizerat, B., Stančáková, A., Goetzman, E., Lam, M. M., Schwer, B., Stevens, R. D., Muehlbauer, M. J., Kakar, S., Bass, N. M., Kuusisto, J., Laakso, M., Alt, F. W., Newgard, C. B., Farese, R. V., Jr, Kahn, C. R., … Verdin, E. (2011). SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Molecular cell, 44(2), 177–190. https://doi.org/10.1016/j.molcel.2011.07.019

5. Kim, T. H., Lee, Y., Lee, Y. S., Gim, J. A., Ko, E., Yim, S. Y., Jung, Y. K., Kang, S., Kim, M. Y.,  Kim, H., Kim, B. H., Kim, J. H., Seo, Y. S., Yim, H. J., Yeon, J. E., Um, S. H., & Byun, K. S.            (2021). Circulating miRNA is a useful diagnostic biomarker for nonalcoholic steatohepatitis in nonalcoholic fatty liver disease. Scientific reports, 11(1), 14639.      https://doi.org/10.1038/s41598-021-94115-6