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

Abstract

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.

Organ Crosstalk and the Modulation of Insulin Signaling

“…Exosomes are generated by invaginations of the plasma membrane, resulting in endocytic vesicles that are released to the extracellular medium [42,43]. Once there, they interact locally or distally with cells from others tissues, inducing changes in cellular function [41,44]. Some of these exosomes seem to regulate insulin sensitivity through two different mechanisms: (i) indirectly by modulating inflammation, or (ii) by direct interaction with insulin-responsive organs.…”

“…Some of these exosomes seem to regulate insulin sensitivity through two different mechanisms: (i) indirectly by modulating inflammation, or (ii) by direct interaction with insulin-responsive organs. Both mechanisms affect insulin sensitivity through interaction with signaling and downstream molecules, such as phosphatidylinositol-3-kinase (PI3K)/Akt, IRS1, and glucose transporter 4 (GLUT-4), or by mediating the activation of inflammation [44,45]. The defective insulin signaling leads to a lower activity of endothelial nitric oxide synthase (eNOS), with a subsequent lower generation of nitric oxide (NO).…”

“…miR-141-3p is responsible for normal Akt phosphorylation upon insulin stimulation. However, its levels are reduced in obese adipocyte exosomes and lead to impaired insulin signaling and glucose uptake in hepatocytes [44,56]. Some miRNAs from adipose tissue also regulate lipid metabolism and insulin signaling in skeletal muscle cells.…”

Circulating microRNA‑135a‑3p in serum extracellular vesicles as a potential biological marker of non‑alcoholic fatty liver disease

“…During lipotoxicity, hepatocytes release a high number of EVs that affect various target cells (including macrophages, Kuffer cells and hepatic stellate cells) and improve key processes associated with NAFLD pathogenesis (such as fibrosis, angiogenesis and immune regulation) ( 38 , 39 ). EVs generated and released during NAFLD progression exhibit a special antigenic composition (such as C-X-C motif chemokine ligand 10, C16:0 ceramide and inositol requiring enzyme 1α), which reflects characteristic pathological changes in its progression, the number of miRNAs and proteins released from the liver increases ( 40 ).…”

Extracellular Vesicles as Drivers of Non-Alcoholic Fatty Liver Disease: Small Particles with Big Impact

“…Microvesicles are larger (100–1000 nm in diameter) and are formed by the outward budding of the plasma membrane. Lastly, apoptotic bodies (50–5000 nm in diameter and usually in the large end of the scale) are released by dying cells [ 3 , 4 ]. However, differences in the techniques used to isolate EVs can make it hard to discriminate specific subpopulations, and consequently this review will not focus on specific subpopulations and collectively refer to all as EVs [ 5 ].…”