Introduction. Metabolic dysfunction-associated steatotic liver disease (MASLD) occupies a leading place in the structure of modern hepatology. A growing body of literature identifies MASLD as a global epidemic. Epigenetics, a new field of biology that studies the influence of external factors on gene activity without changing in deoxyribonucleic acid (DNA) sequences, offers a new perspective on the pathogenesis of MASLD. This review summarizes current knowledge on the epigenetic determinants, such as histone modifications in patients with MASLD.
Methods. We evaluated studies from PubMed, EMBASE, and Scopus using a predefined search string. The following search terms were included, “metabolic dysfunction-associated steatotic liver disease”, “epigenetics”, “histone modifications”, “epigenetic determinants”.
Results. In recent years, the role of histone methylation in MASLD has attracted increasing attention. In a study it was reported that increased trimethylation of the 27th amino acid in histone H3 (H3K27) affects the increased expression of genes involved in lipid synthesis. Enhancer of zeste 2 polycomb repressive complex 2 subunit, identified as the specific methyltransferase responsible for H3K27 methylation, plays a significant role in modulating diverse phenotypes of MASLD and operates through distinct gene targets at different stages of the disease progression [1]. The study reports that these changes are concomitant with variations in the levels of 9th amino acid in Histone H3 (H3K9), H3K27, and 20th amino acid in Histone H4 methylation, underscoring the pivotal role of histone methylation in the initiation and advancement of nonalcoholic steatohepatitis (NASH) [2]. Schuster S. reported that histone methylation exerts influence not only on the acute physiological alterations that underlie the transition from liver steatosis to NASH, but also directly modulates factors implicated in liver inflammation, including hepatocyte lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and other related mechanisms of the MASLD development [3].
Also in a study it was shown that histone demethylation is involved in the development of MASLD. The study demonstrates that lysine demethylase 7A overexpression could erase the H3K9me2 and H3K27me2 repressive markers on the diacylglycerol O-acyltransferase 2 promoter, thereby increasing the expression of diacylglycerol O-acyltransferase 2 and triglycerides accumulation, which, finally, induced hepatic steatosis. As Stearoyl-CoA desaturase 1 and diacylglycerol O-acyltransferase 2 enzymes are potential targets for the treatment of MASLD and clinical trials are ongoing, PHD Finger Protein 2 and lysine demethylase 7A could provide potential therapeutic targets in treating MASLD.
A few studies further suggested that histone acetylation can be a potential target for MASLD. The active phosphorylated form of FTY720/fingolimod, a prodrug treating multiple sclerosis, could reduce fatty acid synthase expression by histone acetylation alteration, inhibit ceramide production and hepatic steatosis in diet-induced MASLD mice [4]. Interestingly, nuclear receptor subfamily 2 group F member 6 expression was increased in the livers of MASLD patients and reduced by metformin treatment in obese mice. Therefore, nuclear receptor subfamily 2 group F member 6 antagonists might offer a therapeutic approach for treating MASLD through histone acetylation. It has also been reported that histone acetylation can be simultaneously involved in the regulation of multiple genes. The homozygous knock-in of a serine-to-alanine mutation at Phospho-Caspase 9 in Liver X receptor alpha could induce liver steatosis but prevent cholesterol accumulation, inflammation and fibrosis, thereby slowing the development from simple hepatic steatosis to NASH [5].
Ubiquitination (the covalent attachment of ubiquitin to acceptor residues in proteins) and sumoylation (the conjugation of any small ubiquitin-like modifiers member to a substrate) are recently demonstrated to be novel forms of histone modification. Studies have reported that post-translational modifications of transcription factors during protein processing play an important role in controlling many biological events [6]. In a study investigating the hepatic gene networks in obese patients with MASLD, hepatic fibrosis signaling was found to be the most significant pathway in the up-regulated MASLD gene cluster, whereas the endoplasmic reticulum stress and protein ubiquitination pathways to be the most significant pathways in the down-regulated MASLD gene cluster [7]. Besides ubiquitination, transcription factors can undergo several types of protein post-translational modifications, including acetylation, phosphorylation, and glycosylation. Currently, little is known about the role of these factors in the development of MASLD. There are also relatively few reports on the role of histone ubiquitination and phosphorylation in the development and progression of MASLD [8].
Conclusions. This review summarizes current knowledge on the epigenetic determinants of MASLD. Genetic variation explains only a small fraction of environmental and hereditary disease risks, whereas epigenetic modifications – such histone modifications – affect the majority of MASLD phenotypes. The research into the potential role of epigenetics in MASLD is still in its infancy and needs to be improved.
References
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