MiR-124 Inhibits Lipid Deposition in Mouse Liver by Targeting the Trib3/Hnf4α Pathway

Non-alcoholic fatty liver disease (NAFLD) arises from dysregulated lipid homeostasis, encompassing imbalances in lipid uptake, synthesis, and catabolism in liver. Despite its global prevalence and clinical impact, effective therapeutic strategies for NAFLD remain elusive. A previous study showed that miR-124 inhibits adipogenic differentiation of murine 3T3-L1 cells by targeting the glucocorticoid receptor (GR). Furthermore, the liver-to-body weight ratio and plasma cholesterol levels were significantly elevated in miR-124 promoter KO mice compared to wildtype controls. Therefore, this study aims to investigate the role of miR-124 in hepatic lipid metabolism and its potential regulatory mechanism. We demonstrate that miR-124 expression is downregulated in hepatocyte lipid deposition model, and its overexpression suppresses lipid deposition by downregulating fatty acid uptake/synthesis genes (e.g., Cd36, Fasn) and upregulating fatty acid β-oxidation/lipolysis/VLDL secretion genes (e.g., Pparα, Cpt-1, Atgl, Apob). Conversely, miR-124 inhibition exacerbates steatosis in vitro. Mechanistically, Tribbles homolog 3 (Trib3) is identified as a direct target of miR-124, and miR-124 negatively regulates Trib3 expression to upregulate hepatocyte nuclear factor 4α (Hnf4α), a liver-specific transcription factor critical for lipid homeostasis. MiR-124 promoter knockout mice confirm that miR-124 deficiency elevates hepatic Trib3, reduces Hnf4α, and promotes lipid accumulation. Collectively, our findings identify the miR-124/Trib3/Hnf4α axis as a novel regulatory pathway in hepatic lipid metabolism, highlighting its potential as a therapeutic target for NAFLD.