Update on genetics and epigenetics in metabolic associated fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming the most frequent chronic liver disease worldwide. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is suggested to replace the nomenclature of NAFLD. For individuals with metabolic dysfunction, multiple NAFLD-related factors also contribute to the development and progression of MAFLD including genetics and epigenetics. The application of genome-wide association study (GWAS) and exome-wide association study (EWAS) uncovers single-nucleotide polymorphisms (SNPs) in MAFLD. In addition to the classic SNPs in PNPLA3, TM6SF2, and GCKR, some new SNPs have been found recently to contribute to the pathogenesis of liver steatosis. Epigenetic factors involving DNA methylation, histone modifications, non-coding RNAs regulations, and RNA methylation also play a critical role in MAFLD. DNA methylation is the most reported epigenetic modification. Developing a non-invasion biomarker to distinguish metabolic steatohepatitis (MASH) or liver fibrosis is ongoing. In this review, we summarized and discussed the latest progress in genetic and epigenetic factors of NAFLD/MAFLD, in order to provide potential clues for MAFLD treatment.

Global Trends of Lipid Metabolism Research in Epigenetics Field: A Bibliometric Analysis from 2012–2021

“…If not controlled in time, NAFLD may even progress to nonalcoholic steatosis hepatitis (NASH) or liver cancer [21]. A growing body of research has also tried to explore epigenetic patterns in the lipid metabolism of NAFLD [20,21]. Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis is an important risk factor for this.…”

“…Cited articles with high centrality were usually important turning points of revolutionary discovery and act as connecting hubs in the research network. Ranked first, "Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis" [20] was published in Nature by Sallam T et al The second and third articles in turn were "m 6 A RNA methylation promotes XIST-mediated transcriptional repression" and "Long Noncoding RNA HULC Modulates Abnormal Lipid Metabolism in Hepatoma Cells through an miR-9-Mediated RXRA Signaling Pathway". Analyzing the journals in which the articles were published, "Nature" appeared more frequently, indicating that pertinent publications in this journal were more favored by scholars.…”

Non-alcoholic fatty liver disease: An emerging epidemic of global importance

“…Gene expression profiling and genome-wide association studies have led to the identification of gene polymorphisms and novel disease pathways that have enriched our understanding of the genetic basis of the disease and may prove to be potential biomarkers of NAFLD progression as well as possible targets of future therapy. [60][61][62][63][64][65] In addition to conventional genetics, epigenetics, an inheritable phenomenon that affects gene expression without changing the DNA order, provides a new perspective on the pathogenesis of NAFLD. The epigenetic changes take place at the transcriptional level and provide a phenotypic connection between the host and the environment.…”

Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

“…Metabolic-associated fatty liver disease (MAFLD) is a relatively new classification of disease to incorporate the metabolic dysfunction that often occurs within patients presenting with non-alcoholic fatty liver disease (NAFLD) ( 1 ). NAFLD has been deemed the world’s leading chronic liver disease leading to liver transplantation or death ( 2 ). Currently, there are no universally approved therapies for NAFLD, and its heterogenous pathology often makes it difficult to identify and treat.…”

“…Thus, MAFLD diagnosis partly overlaps with NAFLD but is independent of alcohol intake and co-existing causes of liver diseases. MAFLD is considered independent of other liver disease etiologies and allows for the identification of fatty liver in patients displaying other metabolic disorders ( 2 , 3 , 5 ). This review describes some of the processes that contribute to the development of MAFLD, processes that are involved in both MAFLD and NAFLD, and the novelty of targeting the liver X receptor (LXR) pathway using tissue selective inverse agonists to alleviate this disease.…”