Hepatic ACE2 Shapes Liver–Islet Communication through Exosomal miR-30c-5p to Preserve β-Cell Function

Background : Progressive dysfunction of pancreatic β-cells is a hallmark of diabetes development. The liver–islet axis is critical for maintaining β-cell function, where hepatocyte-derived exosomes (HExos) transport specific miRNAs and proteins to regulate β-cell gene expression and survival. Angiotensin-converting enzyme 2 (ACE2) is known to modulate systemic metabolic homeostasis and may influence β-cell status by altering exosomal secretion and cargo composition. Methods : We isolated HExos from wild-type (WT-HExos) and ACE2 knockout (ACE2KO-HExos) mice, and assessed their effects in a high-fat diet (HFD)-induced metabolic stress mouse model and palmitate-treated MIN6 cells. Exosomal miRNA profiles were analyzed via high-throughput sequencing, followed by molecular and functional validation of key targets and pathways. Adeno-associated virus-mediated ACE2 or miR-30c-5p overexpression in primary hepatocytes enabled functional rescue experiments in ACE2KO mice. Results : WT-HExos enhancing insulin secretion, preserving β-cell mass, improving glucose tolerance and insulin sensitivity, and mitigating hepatic steatosis and visceral adiposity. In contrast, ACE2KO-HExos exhibited markedly diminished efficacy. Sequencing revealed significant downregulation of miR-30c-5p in ACE2KO-HExos. Mechanistically, miR-30c-5p targets Mitogen-Activated Protein Kinase Kinase Kinase 20 (Map3k20) to inhibit c-Jun N-terminal kinase (JNK) pathway activation, thereby blocking Bax-mediated mitochondrial apoptosis and protecting β-cell function and survival. Exosomes derived from ACE2- or miR-30c-5p-overexpressing hepatocytes restored metabolic and β-cell defects in ACE2KO mice under HFD challenge. Conclusion : This study uncovers hepatic ACE2 as a pivotal regulator of liver–islet inter-organ communication via miR-30c-5p–enriched exosomes. The miR-30c-5p–Map3k20–JNK axis suppresses β-cell mitochondrial apoptosis, preserving β-cell function and offering a promising therapeutic target for diabetes through engineered exosome interventions.