Adipose-specific Sirt3 overexpression alleviated insulin resistance and liver steatosis in high-fat diet-fed male mice by suppressing the transcription of small extracellular vesicle-derived miR-30a-3p.
Adipose small extracellular vesicle-derived miR-30a-3p drives hepatocyte lipotoxicity, suggesting its inhibition as a potential therapy for metabolic dysfunction-associated steatotic liver disease.
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 (HFD)-fed male mice exacerbated insulin resistance and hepatic steatosis in lean recipients. Adipose‑specific Sirt3 overexpression (Sirt3AKI) alleviated insulin resistance and liver steatosis in HFD-fed male mice, whereas adipose‑specific Sirt3 knockdown aggravated these phenotypes. Moreover, adipose sEV miRNAs regulated hepatic lipid metabolism in Sirt3AKI male mice. MicroRNA sequencing identified miR-30a-3p was increased in the circulating sEVs from HFD-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 sEV microRNAs in driving hepatocyte lipotoxicity, and suggest miR-30a-3p inhibition as a promising MASLD therapy.
Zhang et al. (Sat,) conducted a other in Metabolic dysfunction-associated steatotic liver disease (MASLD). Adipose-specific Sirt3 overexpression (Sirt3AKI) vs. Control mice on high-fat diet was evaluated on Hepatic steatosis and insulin resistance. Adipose-specific Sirt3 overexpression alleviated insulin resistance and liver steatosis in high-fat diet-fed male mice by suppressing the transcription of small extracellular vesicle-derived miR-30a-3p.