Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease
Autor: | Qin Pan, Xiao-Lin Liu, Hai-Xia Cao, Feng-Zhi Xin, Huiping Zhou, Ze-Hua Zhao, Rui-Xu Yang, Jian-Gao Fan, Jing Zeng |
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Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Macrophage polarization FOXO1 Exosomes Proinflammatory cytokine Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease medicine Animals Interleukin 6 Protein kinase B Hepatology biology Chemistry Forkhead Transcription Factors Macrophage Activation medicine.disease Rats MicroRNAs Rapamycin-Insensitive Companion of mTOR Protein 030104 developmental biology Integrin alpha M Hepatocytes Cancer research biology.protein 030211 gastroenterology & hepatology Tumor necrosis factor alpha Proto-Oncogene Proteins c-akt Signal Transduction |
Zdroj: | Hepatology. 72:454-469 |
ISSN: | 1527-3350 0270-9139 |
Popis: | 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 In the present study, we reported that lipotoxic injury-induced release of hepatocyte exosomes enriched with miR-192-5p played a critical role in the activation of M1 macrophages and hepatic inflammation. Serum miR-192-5p levels in patients with NAFLD positively correlated with hepatic inflammatory activity score and disease progression. Similarly, the serum miR-192-5p level and the number of M1 macrophages, as well as the expression levels of the hepatic proinflammatory mediators, were correlated with disease progression in high-fat high-cholesterol diet-fed rat models. Lipotoxic hepatocytes released more miR-192-5p-enriched exosomes than controls, which induced M1 macrophage (cluster of differentiation 11b-positive [CD11b+ ]/CD86+ ) 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. |
Databáze: | OpenAIRE |
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