Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

Abstract

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.

Non-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities

“…EVs can contain a wide variety of cargoes [e.g., proteins, lipids, and nucleic acids [coding and noncoding RNA] and mitochondrial DNA] that mediate intercellular communication. In the setting of liver damage, hepatocytes increase EV release, which may act on different target cells leading to pivotal pathobiological processes, such as activation of macrophages, endothelial cells, and HSCs, thus promoting proinflammatory, angiogenic, and fibrotic responses (155)(156)(157)(158). Observations made in mouse models suggest that these EVmediated processes are relevant events in the pathogenesis of both NAFLD and ALD (159)(160)(161).…”

History of Nonalcoholic Fatty Liver Disease

“…Topic Comment 2020-Hernández [215] EVs are emerging as key players in the molecular pathogenesis of NAFLD EVs contain a variety of bioactive molecules (e.g., proteins, lipids, coding and non-coding RNAs and mitochondrial DNA) that exert a key role in cell-to-cell communication via the secretion by different cell types. Stressed/damaged hepatocytes release large quantities of EVs that contribute to the progression of liver disease by affecting inflammation, fibrogenesis and angiogenesis.…”

Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research

“…More recently, it has been found that large quantities of microparticles (MPs) are released by stressed/damaged hepatocytes, contributing to the occurrence of inflammation, fibrogenesis, and angiogenesis; consequently, MPs are considered another promising biomarker for NASH [ 48 ]. By evaluating MPs, it is possible to trace the cells that originated them, so they could be considered non-invasive biomarkers for NASH.…”