Abstract
Background
Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as mediators for intercellular information transfer, delivering various fibrotic factors that impact the function of HSCs in liver fibrosis. In this study, we investigated the role of lipotoxic hepatocyte derived sEV (LTH-sEV) in HSCs activation and its intrinsic mechanisms.
Methods
High-fat diet (HFD) mice model was constructed to confirm the expression of LIMA1. The relationship between LIMA1-enriched LTH-sEV and LX2 activation was evaluated by measurement of fibrotic markers and related genes. Levels of mitophagy were detected using mt-keima lentivirus. The interaction between LIMA1 and PINK1 was discovered through database prediction and molecular docking. Finally, sEV was injected to investigate whether LIMA1 can accelerate HFD induced liver fibrosis in mice.
Results
LIMA1 expression was upregulated in lipotoxic hepatocytes and was found to be positively associated with the expression of the HSCs activation marker α-SMA. Lipotoxicity induced by OPA led to an increase in both the level of LIMA1 protein in LTH-sEV and the release of LTH-sEV. When HSCs were treated with LTH-sEV, LIMA1 was observed to hinder LX2 mitophagy while facilitating LX2 activation. Further investigation revealed that LIMA1 derived from LTH-sEV may inhibit PINK1-Parkin-mediated mitophagy, consequently promoting HSCs activation. Knocking down LIMA1 significantly attenuates the inhibitory effects of LTH-sEV on mitophagy and the promotion of HSCs activation.
Conclusions
Lipotoxic hepatocyte-derived LIMA1-enriched sEVs play a crucial role in promoting HSCs activation in NAFLD-related liver fibrosis by negatively regulating PINK1 mediated mitophagy. These findings provide new insights into the pathological mechanisms involved in the development of fibrosis in NAFLD.
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Details
1 Wujin Hospital Affiliated With Jiangsu University, Department of Laboratory Medicine, Changzhou, China (GRID:grid.440785.a) (ISNI:0000 0001 0743 511X); Jiangsu University, Department of Laboratory Medicine, School of Medicine, Zhenjiang, China (GRID:grid.440785.a) (ISNI:0000 0001 0743 511X)
2 Wujin Hospital Affiliated With Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, China (GRID:grid.440785.a) (ISNI:0000 0001 0743 511X)
3 Wujin Hospital Affiliated With Jiangsu University, Department of Laboratory Medicine, Changzhou, China (GRID:grid.440785.a) (ISNI:0000 0001 0743 511X); Wujin Hospital Affiliated With Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, China (GRID:grid.440785.a) (ISNI:0000 0001 0743 511X); Jiangsu University, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, China (GRID:grid.440785.a) (ISNI:0000 0001 0743 511X)