Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p... : Hepatology (original) (raw)

Original Articles: Steatohepatitis/Metabolic Liver Disease

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

Liu, Xiao‐Lin1,2,†; Pan, Qin1,†; Cao, Hai‐Xia1; Xin, Feng‐Zhi1; Zhao, Ze‐Hua1; Yang, Rui‐Xu1; Zeng, Jing1; Zhou, Huiping3,4; Fan, Jian‐Gao*,1,5

1Department of GastroenterologyXinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

2Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina

3Department of Microbiology and ImmunologyMedical College of VirginiaVirginia Commonwealth UniversityRichmondVA

4McGuire VA Medical CenterRichmondVA

5Shanghai Key Laboratory of Children's Digestion and NutritionShanghaiChina

* Address Correspondence and Reprint Requests to:
Jian‐Gao Fan, Ph.D., M.D.
Department of Gastroenterology, Xinhua Hospital
Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Children's Digestion and Nutrition
1665 Kong Jiang Road
Shanghai 200092, China
E‐mail: [email protected]
Tel.: +86‐21‐2507‐7340

†These authors contributed equally to this work.

Abstract

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.