Characterization of Cellular Sources and Circulating Levels of Extracellular Vesicles in a Dietary Murine Model of Nonalcoholic Steatohepatitis

Li, Jia-hui; Liu, Huimin; Mauer, Amy S.; Lucien, Fabrice; Raiter, Abagail M.; Bandla, Harikrishna; Mounajjed, Taofic; Yin, Ziying; Glaser, Kevin J.; Yin, Meng; Malhi, Harmeet

doi:10.1002/hep4.1404

Cited by 42 publications

(48 citation statements)

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“…In NASH models, circulating EVs also differ in their cell of origin. EVs from adipocytes, macrophages, neutrophils, and platelets are reported to be elevated . Mechanistic studies have demonstrated that both microvesicles and exosomes are released by lipotoxic hepatocytes using distinct cell signaling pathways.…”

Section: Intercellular and Interorgan Crosstalkmentioning

confidence: 99%

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Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.

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Section: Intercellular and Interorgan Crosstalkmentioning

confidence: 99%

“…EVs from adipocytes, macrophages, neutrophils, and platelets are reported to be elevated. (104) Mechanistic studies have demonstrated that both microvesicles and exosomes are released by lipotoxic hepatocytes using distinct cell signaling pathways. LPC-stimulated EV release was dependent on mixed lineage kinase 3.…”

Section: Extracellular Vesiclesmentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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“…In the plasma samples of the NASH mice model, there are significant enrichments of EVs derived from different types of cells [45]. In this study [45], the hepatocyte-EVs are enriched as early as at 10 weeks of high-fat feeding compared with the inflammatory EVs derived from the macrophages, and these hepatocyte-EVs are significantly correlated with NASH development. However, due to the limited findings available, the interpretation of these data should be viewed with caution.…”

Section: Extracellular Vesicles (Evs): Adipocyte-derived Evs In Nafldmentioning

confidence: 53%

“…These circulating adipocyte-EVs caused the accumulations of the inflammatory monocytes in the blood and the adipose tissues of the normal mice [44]. In the plasma samples of the NASH mice model, there are significant enrichments of EVs derived from different types of cells [45]. In this study [45], the hepatocyte-EVs are enriched as early as at 10 weeks of high-fat feeding compared with the inflammatory EVs derived from the macrophages, and these hepatocyte-EVs are significantly correlated with NASH development.…”

Section: Extracellular Vesicles (Evs): Adipocyte-derived Evs In Nafldmentioning

confidence: 99%

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum of liver damage disease from a simple fatty liver (steatosis) to more severe liver conditions such as non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Extracellular vesicles (EVs) are a heterogeneous group of small membrane vesicles released by various cells in normal or diseased conditions. The EVs carry bioactive components in their cargos and can mediate the metabolic changes in recipient cells. In the context of NAFLD, EVs derived from adipocytes are implicated in the development of whole-body insulin resistance (IR), the hepatic IR, and fatty liver (steatosis). Excessive fatty acid accumulation is toxic to the hepatocytes, and this lipotoxicity can induce the release of EVs (hepatocyte-EVs), which can mediate the progression of fibrosis via the activation of nearby macrophages and hepatic stellate cells (HSCs). In this review, we summarized the recent findings of adipocyte- and hepatocyte-EVs on NAFLD disease development and progression. We also discussed previous studies on mesenchymal stem cell (MSC) EVs that have garnered attention due to their effects on preventing liver fibrosis and increasing liver regeneration and proliferation.

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“…Studies carried out in mouse models of NASH have shown that total circulating EVs and particularly hepatocyte-derived EVs are elevated early in the disease process, while other cell-derived EVs (e.g., macrophage-and neutrophil-derived EVs) appear in the circulation later, likely reflecting the ongoing inflammatory process [65,76]. Proteomic profiling of circulating EVs in experimental NAFLD has been demonstrated to allow differentiation between NAFLD vs. control animals [17].…”

Section: Evs In Nafldmentioning

confidence: 99%

Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

Hernández

Arab

Reyes

et al. 2020

Cells

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In recent years, knowledge on the biology and pathobiology of extracellular vesicles (EVs) has exploded. EVs are submicron membrane-bound structures secreted from different cell types containing a wide variety of bioactive molecules (e.g., proteins, lipids, and nucleic acids (coding and non-coding RNA) and mitochondrial DNA). EVs have important functions in cell-to-cell communication and are found in a wide variety of tissues and body fluids. Better delineation of EV structures and advances in the isolation and characterization of their cargo have allowed the diagnostic and therapeutic implications of these particles to be explored. In the field of liver diseases, EVs are emerging as key players in the pathogenesis of both nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD), the most prevalent liver diseases worldwide, and their complications, including development of hepatocellular carcinoma. In these diseases, stressed/damaged hepatocytes release large quantities of EVs that contribute to the occurrence of inflammation, fibrogenesis, and angiogenesis, which are key pathobiological processes in liver disease progression. Moreover, the specific molecular signatures of released EVs in biofluids have allowed EVs to be considered as promising candidates to serve as disease biomarkers. Additionally, different experimental studies have shown that EVs may have potential for therapeutic use as a liver-specific delivery method of different agents, taking advantage of their hepatocellular uptake through interactions with specific receptors. In this review, we focused on the most recent findings concerning the role of EVs as new structures mediating autocrine and paracrine intercellular communication in both ALD and NAFLD, as well as their potential use as biomarkers of disease severity and progression. Emerging therapeutic applications of EVs in these liver diseases were also examined, along with the potential for successful transition from bench to clinic.

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Characterization of Cellular Sources and Circulating Levels of Extracellular Vesicles in a Dietary Murine Model of Nonalcoholic Steatohepatitis

Cited by 42 publications

References 53 publications

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

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