Exosomes in liver pathology

Sato, Keisaku; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco

doi:10.1016/j.jhep.2016.03.004

Cited by 159 publications

(150 citation statements)

References 44 publications

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“…Exosomes are considered important mediators of cell-cell communication by delivering the information they carry to neighboring cells and through their role in liver pathology (20). In the liver, some exosomes that include miRNAs take part in the pathogenesis of liver fibrosis by modulating the epigenetic regulation of HSC (21).…”

Section: Discussionmentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

143

157

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Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor ␤ (TGF-␤) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection.IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCVinfected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-␤ pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection. KEYWORDS hepatitis C virus, exosomes, miRNAs, liver fibrosis, hepatic stellate cells, microRNA H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus with a genome size of 9.6 kb that encodes several structural and nonstructural proteins. About 170 million people are infected with HCV worldwide. Chronic HCV infection often results in the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCVassociated liver fibrosis is a key pathological process leading to liver cirrhosis and HCC (1, 2), although the underlying mechanisms of disease progression remain unclear. Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis (3). Liver injury is characterized by a phenotypic and functional transformation of normally

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Section: Discussionmentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

143

157

View full text Add to dashboard Cite

show abstract

“…EVs contain cargo mediators inside, such as proteins, DNAs, and RNAs, and donor cells can transfer those mediators into recipient cells by secreting EVs. This EV‐mediated cell‐to‐cell communication plays a vital role in the pathophysiology of liver diseases . For example, hepatocytes secrete elevated numbers of EVs during lipid‐induced damage, and these EVs contain tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) .…”

Section: Therapeutic Potentials Of Extracellular Vesiclesmentioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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“…Blockage of the CXCL1 receptor CXCR1/2 ameliorated alcoholic steatohepatitis in mice (14). In addition to chemokines, extracellular vesicles (EVs) are new players in cellto-cell communication and play an important role in promoting inflammation and neutrophil infiltration in a variety of diseases (15,16), including liver diseases (17)(18)(19)(20)(21)(22)(23)(24)(25). EVs are nanometer-sized, membrane-bound extracellular milieu vesicles derived from cells (17).…”

Section: Introductionmentioning

confidence: 99%

“…The functions of EVs are mediated by delivering their contents from one cell to another. For example, stressed hepatocytes can activate macrophages via the release of EVs that contain lipids, proteins, chemokines, and nucleic acids (e.g., mitochondrial DNA [mtDNA]) (17)(18)(19)(20)(21)(22)(23)(24)(25). However, whether EVs also contribute to the elevation of circulating and hepatic neutrophils induced by acute-on-chronic alcoholic liver injury in human and mice remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

Cai¹,

Xu²,

Koritzinsky³

et al. 2017

JCI Insight

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Exosomes in liver pathology

Cited by 159 publications

References 44 publications

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

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