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

Adipose tissue dysfunction results in hepatic lipid overload, driving the progression of liver steatosis and non-alcoholic steatohepatitis. The involvement of adipose tissue-derived small extracellular vesicles (sEVs) in initiating and propagating nonalcoholic fatty liver disease (NAFLD) remains unexplored. Herein, we unveiled that transplanting adipose tissue from high-fat diet (HFD)-fed mice exacerbated insulin resistance and liver steatosis in lean mice, and Sirt3 expression was markedly reduced in adipose tissue from both NAFLD patients and murine NAFLD models. Interestingly, fat-specific Sirt3 overexpression (Sirt3AKI) mice enhanced insulin sensitivity and improved liver steatosis under HFD feeding. Furthermore, adipose tissue-derived sEVs were found to regulate hepatic lipid metabolism in Sirt3AKI mice. In vitro studies demonstrated that Sirt3 overexpressing adipocytes (Sirt3OE) released sEVs to ameliorate lipid accumulation in palmitic acid/oleic acid (P/O)-stimulated hepatocytes. 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.