| Sumari: | Plant-derived exosome-like nanovesicles carry a variety of bioactive substances and have multiple health benefits. Pomegranate (Punica granatum) is a popular fruit with hepatoprotective effects. However, the effects of pomegranate-derived exosome-like nanovesicles (PENs) on nonalcoholic fatty liver disease (NAFLD) are still unknown. Here, PENs were successfully isolated and characterized, and found to be internalized by HepG2 cells. Interestingly, PENs survived gastrointestinal environment and ameliorated lipid accumulation as well as mitochondrial dysfunction in palmitic acid (PA)-treated HepG2 cells. Importantly, oral administration of PENs accumulated in the liver of mice and effectively alleviated high-fat diet (HFD)-induced NAFLD by improving mitochondrial function, as evidenced by improvements of ATP content, mitochondrial complex I activity and oxidative stress. Moreover, PENs restored SIRT3/SOD2 signaling and improved SOD2 activity in the liver of HFD-fed mice. These findings provide new mechanistic insights into pomegranate’s hepatoprotection and demonstrate the therapeutic potential of PENs for NAFLD.
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