Adipocyte exosomal-derived microRNA30a-3p exacerbates liver steatosis in obese mice

Conversely, sEVs derived from NAFLD patients exacerbated hepatic lipid accumulation in HFD-fed Sirt3AKI mice. MicroRNA sequencing further identified a significant decrease in miR-30a-3p levels in sEVs derived from Sirt3OE adipocytes. Fat-specific miR-30a-3p overexpression worsened hepatic steatosis in HFD-fed Sirt3AKI mice.

In contrast, engineered sEVs loaded with miR-30a-3p antagonist or miR-30a-3p inhibition robustly enhanced insulin sensitivity and mitigated hepatic accumulation in HFD-fed mice. Mechanistically, CHIP-qPCR and CHIP-sequencing analyses revealed that Sirt3 suppressed miR-30a-3p transcription through H3K56 acetylation. Dual-luciferase reporter assays validated Beclin1 as a bona fide target mRNA of miR-30a-3p.

Taken together, these findings highlight the critical role of exosomal microRNAs in mediating adipocyte-hepatocyte crosstalk, provide novel insights into the mechanisms underlying lipotoxicity in hepatocytes, and suggest miR-30a-3p inhibitor could be a therapeutic agent for NAFLD.