Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease

BACKGROUND AND AIMS: Hepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs (miRs), proteins, and lipids. The role of exosomes in crosstalk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored. APPROACH AND RESULTS: ) activation and increase of inducible nitric oxide synthase, interleukin 6, and tumor necrosis factor alpha expression. Furthermore, hepatocyte-derived exosomal miR-192-5p inhibited the protein expression of the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), which further inhibited the phosphorylation levels of Akt and forkhead box transcription factor O1 (FoxO1) and resulted in activation of FoxO1 and subsequent induction of the inflammatory response. CONCLUSIONS: Hepatocyte-derived exosomal miR-192-5p plays a critical role in the activation of proinflammatory macrophages and disease progression of NAFLD through modulating Rictor/Akt/FoxO1 signaling. Serum exosomal miR-192-5p represents a potential noninvasive biomarker and therapeutic target for nonalcoholic steatohepatitis.