Exosomal transfer of miR-375-3p from pancreatic β cells to hepatocytes impairs hepatic glycogenesis via Rbpj repression

BACKGROUND Glucotoxic pancreatic β cells impair glycogenesis of hepatocytes, with exosomes serving as novel mediators. miR-375-3p is the most abundant miRNA in the pancreas and critical for β-cell function, but whether it plays a role in pancreas-liver crosstalk remains unclear. AIM To investigate the role of miR-375- 3p, a key regulator of pancreatic β cells, in remotely regulating hepatocyte glycogenesis via exosomes. METHODS Mice fed a high-fat diet (HFD) served as animal models, and mouse primary pancreatic islet cells and the β-cell line MIN-6 were used as cellular models. miR-375- 3p expression in pancreatic cells, hepatocytes and exosomes was detected in both animal and cellular models. Transwell assays, exosome treatment, and exosome-depleted supernatant culture were used to investigate the role of exosomal miR-375-3p in pancreatic-hepatocyte crosstalk. The AKT/GSK signaling pathway and hepatic glycogen content were used as indicators to evaluate hepatocyte glycogenesis. Luciferase reporter assays were used to evaluate the downstream targets of miR-375-3p. RESULTS Increased levels of miR-375-3p were observed in both the pancreas and liver of HFD-fed mice. In contrast to the in vivo results, high-glucose treatment exclusively increased the expression of miR-375-3p in pancreatic cells but had no effect on hepatocytes. Furthermore, hepatocytes treated with the supernatant and exosomes from glucotoxic pancreatic cells presented elevated expression of miR-375-3p. Additionally, exosomal transfer of miR-375-3p from pancreatic cells to hepatocytes suppressed the AKT/GSK signaling pathway, thereby reducing the hepatic glycogen content. Luciferase analysis indicated that the recombination signal binding protein for the immunoglobulin kappa J region (Rbpj) is a target gene of miR-375-3p. Rbpj inhibition impaired hepatic glycogenesis, and Rbpj overexpression reversed the effect on glycogenesis induced by miR-375- 3p. CONCLUSION Pancreatic cell-derived miR-375- 3p can be delivered to hepatocytes via exosomes and inhibits hepatocyte glycogenesis by targeting Rbpj.