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Adipocyte small extracellular vesicle-derived microRNA-30a-3p exacerbates hepatic steatosis in high fat diet-fed male mice

ABSTRACT: Adipose tissue dysfunction drives hepatic lipid overload in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the involvement of adipose tissue-derived small extracellular vesicles (sEVs) remains unclear. Herein, we showed that transplanting adipose tissue from high‑fat diet-fed male mice exacerbated insulin resistance and hepatic steatosis in lean recipients. Adipose‑specific Sirt3 overexpression (Sirt3AKI) alleviated insulin resistance and liver steatosis in high fat diet-fed male mice, whereas adipose‑specific Sirt3 knockdown aggravated these phenotypes. Moreover, adipose‑derived sEVs play key roles in hepatic lipid metabolism by delivering miRNAs in Sirt3AKI male mice. MicroRNA sequencing identified miR-30a-3p was increased in the circulating sEVs from high fat diet-fed male mice, while decreased in sEVs from Sirt3OE adipocytes and Sirt3AKI male mice. Mechanistically, miR‑30a‑3p promoted hepatic steatosis by targeting Becn1; this process was suppressed when Sirt3 downregulated miR‑30a‑3p transcription via deacetylation of H3K56. These findings highlight the critical role of adipose sEVs microRNAs in driving hepatocyte lipotoxicity, and suggest miR-30a-3p inhibition could be a therapeutic intervention for MASLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE325068 | GEO | 2026/03/17

REPOSITORIES: GEO

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Project description: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.

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Adipocyte small extracellular vesicle-derived microRNA-30a-3p exacerbates hepatic steatosis in high fat diet-fed male mice

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