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.

Keywords: NAFLD; adipocyte; apoptotic bodies; cell to cell communication; exosome; fibrosis; hepatocyte; insulin resistance; microvesicles.

Figure 1

Schematic representation of the exosome biogenesis. Abbreviation: endosomal sorting complex required for transport (ESCRT), intraluminal vesicles (ILV), multivesicular bodies (MVBs).

Figure 2

Schematic representation of the microvesicle biogenesis. Abbreviation: ADP-ribosylation factor-6 (ARF6), microRNA (miRNA), phospholipase D (PLD).

Figure 3

Schematic representation of the microvesicle biogenesis.

Figure 4

Illustration of the extracellular vesicles’ involvement in NAFLD development. Adipocyte-derived extracellular vesicles mediate the endocrine effects in hepatocytes, hepatic stellate cells, and macrophages (Kuffer cells) in the early phase of the NAFLD development. The disease progression becomes worse when the hepatocytes release their extracellular vesicles that promote the formation of fibrosis. The green arrow represents upregulation, and the red arrow represents downregulation. Abbreviation: α-smooth muscle actin (α-SMA), C-X-C-motif chemokine 10 (CXCL10), interleukin-1 β (IL-1β), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-9 (MMP-9), mitochondrial DNA (mtDNA), non-alcoholic fatty liver disease (NAFLD), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NLR family pyrin domain containing 3 (NLRP3), peroxisome proliferator-activated receptor delta (PPARD), peroxisome proliferator-activated receptor gamma (PPAR-γ), plasminogen activator inhibitor-1 (PAI-1), sphingosine-1-phosphate (S1P), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), tissue inhibitor of matrix metalloproteinase-4 (TIMP-4), TNF-related apoptosis-inducing ligand (TRAIL), and tumor necrosis factor-alpha (TNF-α).