GLUT5-Driven Gut-Liver Axis Injury Mediating Olanzapine-Induced NAFLD and Dapagliflozin Intervention.

Abstract

OBJECTIVE: Drugs are an important cause of non-alcoholic fatty liver disease (NAFLD), and olanzapine is the main drug that leads to NAFLD. However, the mechanism by which this drug causes NAFLD is still unclear at present. We previously found that dapagliflozin had certain intervention effect on patients with NAFLD. This study aimed to explore the mechanism of olanzapine-induced NAFLD and the intervention effect of dapagliflozin. METHODS: Twenty-four female wistar rats were classified into control (NC) group, olanzapine (OLA) group, and dapagliflozin intervention (DAP) group for a total of 12&#xa0;weeks of intervention. This study explored the specific mechanism of olanzapine-induced NAFLD and potential treatment method from dapagliflozin through transcriptomics, molecular biology, and pathological staining methods in animal models. RESULTS: The transcriptome and immunohistochemistry studies of the intestine and liver revealed the high expression of GLUT5 in both tissues (< 0.01). Olanzapine induced gut-liver axis injury via GLUT5/AMPK/mTOR (< 0.05 or< 0.01). Dapagliflozin reversed GLUT5/AMPK/mTOR to improve intestinal barrier injury, NAFLD and hepatic fibrosis (< 0.05 or< 0.01). CONCLUSION: The study discovered for the first time that GLUT5/AMPK/mTOR drived gut-liver axis injury mediating olanzapine-induced NAFLD and dapagliflozin intervention could reverse GLUT5/AMPK/mTOR-driven gut-liver axis injury ameliorating olanzapine-induced NAFLD. This provided a new understanding of the occurrence of olanzapine-induced NAFLD and offered a reference plan for its clinical intervention.