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Review
. 2023 Aug 16;24(16):12864.
doi: 10.3390/ijms241612864.

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease

Ioanna Aggeletopoulou  1 , Maria Kalafateli  2 , Efthymios P Tsounis  1 , Christos Triantos  1
Affiliations
Review

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease

Ioanna Aggeletopoulou et al. Int J Mol Sci. .

Abstract

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder.

Keywords: DNA methylation; epigenetic regulation; epigenetics; histone modification; lean NAFLD; nonalcoholic fatty liver disease; noncoding RNAs; nonobese NAFLD.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DNA methylation in lean NAFLD. DNA methylation is a post-translational modification through which methyl groups (Me) are added to DNA on the CpG islands and regulates transcriptional gene expression, particularly gene silencing. The rs7946-PEMT genetic variant in the PEMT gene has been related to increased risk for lean NAFLD, whereas Val175Met-PEMT has increased incidence in lean NASH patients. Differential methylation regions and differentially methylated genes have been observed in both lean and obese mice during the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma. This figure was generated using BioRender, available online at: https://biorender.com (accessed on 25 July 2023). Abbreviations: DNMTs, DNA methyltransferases; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; PEMT, phosphatidylethanolamine N-methyltransferase; NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; PE, phosphatidylethanolamine; PC, phosphatidylcholine; DMRs, differentially methylated regions; HCC, hepatocellular carcinoma.
Figure 2
Figure 2
Modifications of histones. A major association between chromatin modifications and metabolic imbalance has been observed in lean individuals with MAFLD. Methylation and acetylation of histones have resulted in the stimulation of genes closely related to lipogenic and inflammatory processes and the downregulation of genes associated with fatty acid oxidation. In lean MAFLD, a significant reduction in macroH2A1.1 and macroH2A1.2 histone variants has been observed. Macrophage epigenome modifications in lean MAFLD downregulate the bile acid signaling and induce an inflammatory response, leading to more severe liver disease. This figure was generated using BioRender, available online at: https://biorender.com (accessed on 25 July 2023). Abbreviations: HATs, histone acetyltransferases; KDMs, histone lysine demethylases; TF, transcription factor; MAFLD, metabolic-associated fatty liver disease; TLR, Toll-like receptor; LPS, lipopolysaccharide.
Figure 3
Figure 3
miRNA structure and biogenesis. MicroRNA (miRNA) genes, a subgroup of small noncoding RNAs, are typically transcribed by an RNA polymerase II within the nucleus to generate pri-miRNA transcripts. The microprocessor complex, comprising the dimeric RNA-binding protein DGCR8 and the RNase III enzyme Drosha, facilitates the cleavage of pri-miRNA, producing the pre-miRNA precursor. Subsequently, exportin 5 (XPO5) transports the pre-miRNA to the cytoplasm. In the cytoplasm, the pre-miRNA is cleaved into a mature double-stranded miRNA by the Dicer enzyme and the transactivation response element RNA-binding protein (TRBP) complex. Upon maturation, the mature miRNA becomes part of the miRNA-associated multiprotein RNA-induced silencing complex (mi-RISC). Following that, the mature miRNA binds to complementary regions on the target mRNA, guiding and modulating its expression through base pairing. Generally, mature miRNA binds to specific mRNA 3′-untranslated sequences (3′-UTR) via partially complementary regions, leading to the inhibition of mRNA translation into proteins. However, if miRNA and mRNA exhibit high complementarity, this can result in the cleavage of the target mRNA. This figure was generated using BioRender, available online at: https://biorender.com (accessed on 25 July 2023). Abbreviations: miRNA, microRNA; pol II, polymerase II; DGCR8, DGCR8 microprocessor complex subunit; miRISC, miRNA-induced silencing complex; TRBP, transactivation response element RNA-binding protein.
Figure 4
Figure 4
Role of miRNAs in lean NAFLD. Several miRNAs have been implicated in the pathogenesis of lean NAFLD and have been suggested as potential biomarkers for lean NAFLD diagnosis and prognosis. This figure was generated using BioRender, available online at: https://biorender.com (accessed on 25 July 2023). Abbreviations: miRNA, microRNA; NAFLD, nonalcoholic fatty liver disease; TNF, tumor necrosis factor; p53, protein P53; PPARa, peroxisome proliferator-activated receptor alpha; msRNA, microRNA-sized small RNA.
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