Emerging role of extracellular vesicles in liver diseases

Abstract

Extracellular vesicles (EVs) are membrane-defined nanoparticles released by most cell types. The EVs released by cells may differ quantitatively and qualitatively from physiological states to disease states. There are several unique properties of EVs, including their proteins, lipids and nucleic acid cargoes, stability in circulation, and presence in biofluids, which make them a critical vector for cell-to-cell communication and impart utility as a biomarker. EVs may also serve as a vehicle for selective cargo secretion. Similarly, EV cargo may be selectively manipulated for targeted therapeutic delivery. In this review an overview is provided on the EV classification, biogenesis, and secretion pathways, which are conserved across cell types. Next, cargo characterization and effector cell responses are discussed in the context of nonalcoholic steatohepatitis, alcoholic hepatitis, and acetaminophen-induced liver injury. The review also discusses the potential biomarker and therapeutic uses of circulating EVs.

Keywords: alcoholic hepatitis; exosome; microvesicle; nanoparticle; nonalcoholic steatohepatitis.

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the author.

Figures

Graphical abstract

Fig. 1.

Extracellular vesicles (EVs) in health and disease. Salutary properties of healthy hepatocyte-derived EVs in maintaining liver homeostasis by promoting repair and regeneration have been recently described. This is in contrast to EVs originating from stressed hepatocytes in disease states, which activate injury, inflammation, and fibrotic responses in recipient cells.

Fig. 2.

Extracellular vesicle release along a continuum of stress responses. Healthy and stressed hepatocytes release extracellular vesicles (EVs) into the extracellular space that can be classified into exosomes and microvesicles on the basis of their cellular biogenesis pathways. Exosomes are derived from the intraluminal vesicles of multivesicular bodies (MVB), whereas microvesicles are released by direct budding from the plasma membrane. Apoptotic cells release apoptotic bodies which are formed by plasma membrane blebbing and may contain nuclear material. Cell stress, one feature of which is EV release, can eventually result in apoptosis; thus, both EV release and apoptosis can be viewed as a continuum of responses to cellular stress.

Fig. 3.

Mechanism of lipotoxic extracellular vesicle (EV) release. Saturated fatty acids, including palmitate and the phospholipid lysophosphatidyl choline (LPC) stimulate the release of heterogeneous EVs from hepatocytes. The endoplasmic reticulum (ER) stress sensor inositol requiring enzyme 1α (IRE1α) is activated by palmitate, leading to the transcriptional upregulation of de novo ceramide synthesis and the release of ceramide enriched EVs. The ceramide transport protein StAR-related lipid transfer protein 11 (STARD11) mediates efficient trafficking of ceramide from the ER to the multivesicular bodies (MVB) leading to EV release. The stress kinase mixed lineage kinase 3 (MLK3) and tumor necrosis factor-like apoptosis inducing ligand receptor (TRIALR) also mediate transmission of lipotoxic stress signals into EV release via caspase 3 activation and rho-associated protein kinase 1 (ROCK1) activation.