BACKGROUND Glucotoxic pancreaticβcells impair glycogenesis of hepatocytes,with exosomes serving as novel mediators.miR-375-3p is the most abundant miRNA in the pancreas and critical forβ-cell function,but whether it...BACKGROUND Glucotoxic pancreaticβcells impair glycogenesis of hepatocytes,with exosomes serving as novel mediators.miR-375-3p is the most abundant miRNA in the pancreas and critical forβ-cell function,but whether it plays a role in pancreasliver crosstalk remains unclear.AIM To investigate the role of miR-375-3p,a key regulator of pancreaticβcells,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 theβ-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.展开更多
Diabetes is a growing global health concern,calling for improved diagnostic and therapeutic strategies.Of the emerging possible biomarkers,microRNA 375(miR-375)has gained attention for its pivotal role in pancreaticβ...Diabetes is a growing global health concern,calling for improved diagnostic and therapeutic strategies.Of the emerging possible biomarkers,microRNA 375(miR-375)has gained attention for its pivotal role in pancreaticβcell development and function,and its altered blood levels followingβcell injury.This review summarizes the current knowledge on the role of miR-375 in insulin regulation,its correlation with diabetes,and its clinical potential.Despite its well-known role inβcell biology,literature analyses have failed to reveal a consistent correlation between the circulating levels of miR-375 and diabetes.A key limitation lies in the lack ofβcell specificity of miR-375,along with its modulation by diabetes-related complications,which influences circulating levels of the miRNA.Moreover,the absence of large-scale,standardized clinical studies undermines the comparability of existing data.Despite these limits,the literature analysis clearly indicates the need to expand research into miR-375 modulation strategies in humans,as integrating miR-375 with other diagnostic and therapeutic technologies could enhance its clinical relevance.Such strategies may support more personalized and timely interventions for treating diabetes and its complications,ultimately benefiting patient outcomes and contributing to the sustainability of global healthcare systems.展开更多
基金Supported by Beijing Natural Science Foundation,No.7252124National High Level Hospital Clinical Research Funding,No.BJ-2024-219,No.BJ-2025-125 and No.BJ-2023-236+1 种基金National Natural Science Foundation of China,No.82370584,No.82470395 and No.81600618National Key R&D Program of China,No.2021YFE0114200.
文摘BACKGROUND Glucotoxic pancreaticβcells impair glycogenesis of hepatocytes,with exosomes serving as novel mediators.miR-375-3p is the most abundant miRNA in the pancreas and critical forβ-cell function,but whether it plays a role in pancreasliver crosstalk remains unclear.AIM To investigate the role of miR-375-3p,a key regulator of pancreaticβcells,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 theβ-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.
文摘Diabetes is a growing global health concern,calling for improved diagnostic and therapeutic strategies.Of the emerging possible biomarkers,microRNA 375(miR-375)has gained attention for its pivotal role in pancreaticβcell development and function,and its altered blood levels followingβcell injury.This review summarizes the current knowledge on the role of miR-375 in insulin regulation,its correlation with diabetes,and its clinical potential.Despite its well-known role inβcell biology,literature analyses have failed to reveal a consistent correlation between the circulating levels of miR-375 and diabetes.A key limitation lies in the lack ofβcell specificity of miR-375,along with its modulation by diabetes-related complications,which influences circulating levels of the miRNA.Moreover,the absence of large-scale,standardized clinical studies undermines the comparability of existing data.Despite these limits,the literature analysis clearly indicates the need to expand research into miR-375 modulation strategies in humans,as integrating miR-375 with other diagnostic and therapeutic technologies could enhance its clinical relevance.Such strategies may support more personalized and timely interventions for treating diabetes and its complications,ultimately benefiting patient outcomes and contributing to the sustainability of global healthcare systems.
