MicroRNA Mediators in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic disorders characterised by excessive lipid accumulation in the absence of significant alcohol intake, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Mounting evidence implicates microRNAs (miRNAs)—short non-coding RNA molecules that regulate gene expression at the post-transcriptional level—as pivotal mediators of lipid homeostasis, inflammation and fibrogenesis in NAFLD. Dysregulated miRNA expression contributes to aberrant lipid synthesis, impaired mitochondrial β-oxidation and chronic inflammation by targeting key metabolic enzymes, transcription factors and signalling pathways. For example, specific miRNAs modulate the activity of AMP-activated protein kinase (AMPK), a central energy sensor, as well as nuclear receptors such as peroxisome proliferator-activated receptor alpha (PPARα) and chromatin regulators including Sirtuin 1 (SIRT1). Beyond intracellular effects, miRNAs are exported in extracellular vesicles to exert endocrine-like functions, shaping adipose tissue insulin sensitivity and systemic inflammatory responses. Collectively, these observations position miRNA pathways both as biomarkers for disease staging and as promising targets for therapeutic intervention in NAFLD and its progressive form, NASH.

Research from Nature Portfolio

Recent mechanistic work has identified the MAIP1/miR-27b axis as a critical regulator of hepatic lipid accumulation. In human and murine hepatocytes, overexpression of miR-27b silences MAIP1 and other targets, leading to triglyceride deposition, whereas restoration of MAIP1 counteracts steatosis. Complementary in vivo studies demonstrate downregulation of Maip1 in high-fat diet models, highlighting the therapeutic potential of modulating this miRNA–target interaction. Foundational research on miR-34a has further elucidated its role in steatosis by direct repression of PPARα and SIRT1. Inhibiting miR-34a in cellular and murine NAFLD models enhances fatty acid oxidation via PPARα, activates AMPK through SIRT1 upregulation and reduces lipid deposition, underscoring a convergent network of miRNA-driven control points within hepatic lipid metabolism.

MicroRNA Mediators in Non-Alcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in microrna mediators in non-alcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

microRNA (miRNA): Short non-coding RNA molecules (~22 nucleotides) that post-transcriptionally regulate gene expression by binding complementary sequences in target messenger RNAs.

Non-alcoholic fatty liver disease (NAFLD): A spectrum of liver disorders characterised by hepatic fat accumulation in individuals who consume little or no alcohol.

Non-alcoholic steatohepatitis (NASH): An advanced form of NAFLD marked by hepatic inflammation, hepatocyte injury and varying degrees of fibrosis.

Extracellular vesicles (EVs): Membrane-bound particles released by cells that transport proteins, lipids and nucleic acids, including miRNAs, to mediate intercellular communication.

AMP-activated protein kinase (AMPK): A central energy sensor kinase that regulates metabolic pathways in response to cellular energy status, balancing anabolic and catabolic processes.

Peroxisome proliferator-activated receptor alpha (PPARα): A nuclear receptor that governs expression of genes involved in fatty acid transport and β-oxidation.

Sirtuin 1 (SIRT1): A NAD⁺-dependent deacetylase that modulates metabolic and stress-response pathways, including activation of AMPK and regulation of lipid metabolism.

References

1. MicroRNA regulation of AMPK in nonalcoholic fatty liver disease. Experimental & Molecular Medicine (2023).
2. Extracellular Vesicles miRNome Profiling Reveals miRNAs Engagement in Dysfunctional Lipid Metabolism, Chronic Inflammation and Liver Damage in Subjects With Metabolic Dysfunction‐Associated Steatotic Liver Disease. Alimentary Pharmacology & Therapeutics (2025).
3. miR-27b targets MAIP1 to mediate lipid accumulation in cultured human and mouse hepatic cells. Communications Biology (2023).
4. Effect of miR-34a in regulating steatosis by targeting PPARα expression in nonalcoholic fatty liver disease. Scientific Reports (2015).
5. A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition*. Journal of Biological Chemistry (2010).