Mesenchymal stem cells-derived exosomal miR-24-3p ameliorates non-alcohol fatty liver disease by targeting Keap-1

• Published in: Biochemical and biophysical research communications 2022-12, Vol.637, p.331-340
• Main Authors: Du, Xiaolin, Li, Haiyan, Han, Xingjun, Ma, Wenlu
• Format: Article
• Language: English
• Subjects: Animals; Exosome; Humans; Inflammation; Keap-1; Kelch-Like ECH-Associated Protein 1 - genetics; Mesenchymal Stem Cells; Mice; MicroRNAs - genetics; miR-24-3p; MSCs; NAFLD; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - therapy; Palmitates; Reactive Oxygen Species
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.11.012

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with ill-defined etiology and pathogenesis, and no approved effective therapy is presently available. Exosome-dependent intercellular communication has been identified as a potential signaling involved in tissue repair. Unfortunately, the exact influence and underlying mechanism of mesenchymal stem cells (MSCs)-derived exosome (Exo) in modulating fatty liver have not been well determined. Here in our study, in vitro results initially showed that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-derived Exo treatment significantly suppressed lipid accumulation, reactive oxygen species (ROS) generation and inflammatory response in palmitate (PA)-stimulated mouse hepatocytes. Consistently, MSCs-derived Exo administration strongly ameliorated metabolic disorders, hepatic dysfunction and steatosis in high fat diet (HFD)-induced mouse model with NAFLD. Furthermore, Exo derived from MSCs significantly alleviated hepatic lipid metabolism disturbance, inflammation and oxidative stress induced by HFD. Exo treatment resulted in a stronger increase in miR-24-3p expression in hepatocytes. Reducing miR-24-3p in MSCs markedly abrogated the protective effects of Exo in hepatocytes under PA stimulation. Mechanistically, miR-24-3p directly targeted Kelch-like ECH-associated protein 1 (Keap-1), and suppressed its expression. In addition, the effects of MSCs-derived exosomal miR-24-3p to restrain lipid accumulation, ROS generation and inflammation in vitro were largely Keap-1 dependent via Keap-1 depression. Collectively, our study demonstrated that MSCs-derived exosomal miR-24-3p had hepaprotective effects through targeting Keap-1 signaling, providing a potential therapeutic value for NAFLD treatment. [Display omitted] •MSCs-Exo mitigates lipid deposition, ROS production and inflammation in PA-treated hepatocytes.•MSCs-Exo attenuates HFD-induced metabolic disorders and hepatic dysfunction in mice.•MSCs-Exo inhibits lipid accumulation, inflammation and oxidative stress in liver of HFD-fed mice.•MSCs-derived exosomal miR-24-3p reduces lipid deposition, inflammatory response and ROS production in PA-exposed hepatocytes.•MSCs-Exo miR-24-3p and its target Keap-1 regulate PA-induced NAFLD phenotypes in vitro.