osa-miR166g-3p Mimic Reduces Hepatic Triglyceride Accumulation in Mice

Abstract Hepatic triglyceride accumulation reflects an imbalance in hepatic lipid metabolism, and pharmacological approaches that enhance fatty acid utilization may provide a strategy for reducing excessive lipid accumulation in the liver. Here, we evaluated the effects of a synthetic osa-miR166g-3p mimic, corresponding to a microRNA sequence originally identified in Oryza sativa L., on hepatic lipid metabolism in mice and hepatic cell models. Systemic administration of the osa-miR166g-3p mimic reduced hepatic triglyceride levels in mice without significant short-term changes in serum aminotransferase activities, body weight, or adipose tissue weight. In HFD-fed mice, the osa-miR166g-3p mimic significantly reduced hepatic triglyceride content and increased hepatic AMP-activated protein kinase (AMPK) phosphorylation compared with NC mimic treatment. In HepG2 cells, the osa-miR166g-3p mimic increased FAOBlue fluorescence, a cellular readout associated with fatty acid β-oxidation, and increased PPARα and CPT1A expression. These changes were accompanied by increased AMPK phosphorylation. Selected time-dependent transcriptional responses were also observed in NMuLi cells. In addition, target prediction, sequence analysis, and reduced PPP2R5C/Ppp2r5c mRNA expression in HepG2 and NMuLi cells supported PPP2R5C/Ppp2r5c as a predicted candidate target requiring direct validation. Collectively, these findings provide short-term pharmacological proof-of-concept that the osa-miR166g-3p mimic modulates hepatic lipid metabolism in association with fatty acid β-oxidation-related and AMPK-related signaling. Further studies are required to validate its direct molecular target(s), characterize its tissue distribution and pharmacokinetics, and determine its long-term efficacy and safety.