Changes in m6A in Steatotic Liver Disease

Abstract

Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), now replaced by a consensus group as metabolic dysfunction-associated steatotic liver disease (MASLD). While excess nutrition and obesity are major contributors to fatty liver, the underlying mechanisms remain largely unknown and therapeutic interventions are limited. Reversible chemical modifications in RNA are newly recognized critical regulators controlling post-transcriptional gene expression. Among these modifications, N6-methyladenosine (m6A) is the most abundant and regulates transcript abundance in fatty liver disease. Modulation of m6A by readers, writers, and erasers (RWE) impacts mRNA processing, translation, nuclear export, localization, and degradation. While many studies focus on m6A RWE expression in human liver pathologies, limitations of technology and bioinformatic methods to detect m6A present challenges in understanding the epitranscriptomic mechanisms driving fatty liver disease progression. In this review, we summarize the RWE of m6A and current methods of detecting m6A in specific genes associated with fatty liver disease.

Keywords: NAFLD; NASH; RNA modifications; epitranscriptome; fatty liver; m6A.

Figure 1

m6A readers, writers, and erasers (RWE) in NAFLD, based in part on [74] RWE of m6A in mRNA regulate transcript fate. Shown is the METTL3 m6A methyltransferase (writer) complex which includes: METTL3, METT14, WTAP, VIRMA, ZC2H13,RBM15,and HAKAI and the predominant subcellular location and roles of reader proteins, including nuclear RBPS: HNRNPA2B1, HNRNPC, and YTHDC1 and cytoplasmic RBPs: YTHDF1, YTHDF2, YTHDF3, YTHDC2, IGF2BP1, IGF2BP2, and IGF2BP3. ALKBH5 is a specific m6A demethylase, whereas there is controversy as to the specificity of FTO for m6A demethylation as described in the text. The up (red) and down (green) arrows indicate the expression levels generally identified in hepatic disease conditions (see further details in Table 1). Created with BioRender.com.

Figure 2

Number of publications per year including m6A and liver or NAFLD in PubMed.

Figure 3

Role of m6A modifications in lipid metabolism. The liver expression of m6A RWE is perturbed by physiological and disease processes, resulting in changes in m6A levels and subsequently, transcript processing and protein translation regulated in part by m6A readers. Experimental hepatocyte-specific knockout of Mettl3 in mice increased fibrosis and steatosis and downregulated the indicated transcripts [192]. In T2DM patients, glucose increases FTO expression [188]. Overexpression of FTO in HepG2 cells altered the expression of the indicated transcripts which resulted in increased lipid accumulation [190]. Circadian gene disruption in mice increased Mettl3 and Ythdf2 expression which mediated Ppara mRNA decay [184]. CCl₄-induced liver fibrosis in HSCs increased ZC2H13 and decreased FTO increasing m6A levels. YTHDC1 bound to m6A on the NR1D1 transcript, decreasing NR1D1 expression which resulted in disrupted fatty acid regulation, lipid accumulation and liver inflammation [49]. Abbreviations: Enoyl-CoA Hydratase And 3-Hydroxyacyl CoA Dehydrogenase (EHHADH), PPARG Coactivator 1 α (PPARGC1A), Sirtuin 1 (SIRT1), Fatty Acid Synthase (FASN), α-1,3-Mannosyl-Glycoprotein 2-β-N-Acetylglucosaminyltransferase (MGAT1), Stearoyl-CoA Desaturase (SCD1), Microsomal Triglyceride Transfer Protein (MTTP), Apolipoprotein B (APOB), Lipase C, Hepatic Type (LIPC), Peroxisome Proliferator Activated Receptor α (PPARα), Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1). Further details from these studies are provided in the text.