Table 1.
Summary of the reported extracellular vesicles (EVs) from various sources and their clinical importance related to non-alcoholic fatty liver disease (NAFLD).
| Extracellular Vesicles | Cell Source | EVs-Derived Disease Model | Molecular Mediators in the EVs Cargos | Recipient Targets | Interaction | NAFLD Relevance | Reference |
|---|---|---|---|---|---|---|---|
| Exosome | Visceral adipose tissue (VAT) | Leptin-deficient (ob/ob) B6 mice, B6 mice fed high-fat diets | RBP4 | Bone marrow-derived macrophages (BMDM) | Increased production of MCSF, IL-6, and TNF-α | Activation of BMDM macrophages induced insulin resistance | [34] |
| Exosome | VAT | Human, Females with BMI > 30 kg/m2 | MicroRNAs | TGF-β and Wnt/β-catenin signaling | TGF-β signaling and Wnt/β-catenin signaling among the top significant pathways | MicroRNAs in the exosomes derived from the obese visceral adipocytes are predicted to regulate inflammatory and fibrotic signaling pathways | [36] |
| Exosomes | VAT | Human, Females with BMI 35–46 (obese) | - | Hepatocytes and Hepatic stellate cells (HSCs) | Induced the expressions of TIMP-1, TIMP-4, SMAD-3, MMP-9, integrins ανβ-5 and -8 | Dysfunctional ECM regulation in the liver cells due to obese adipocyte exosomes | [37] |
| Exosome | Adipose tissue macrophages (ATM) | C57BL6 mice fed high-fat diets (in vivo), 3T3-L1 adipocytes (in vitro) | MicroRNAs (specifically miR-155) | L6 muscle cells and primary hepatocytes | Enriched miR-155 in the obese ATM-derived exosomes suppressed the expression of its target gene, PPARγ, and the downstream pathways | MicroRNAs cargos of secreted ATM-derived exosomes induced insulin resistance and glucose intolerance | [38] |
| Exosome | ATM | C57/BL6 mice fed high-fat diets | MicroRNAs (specifically miR-29a) | PPARD | MiR-29a interacts with PPARD to promote obesity-induced insulin resistance | ATM-derived exosomal miR-29a impairs insulin sensitivity in vitro and in vivo | [39] |
| Exosome | Adipose tissue | C57BL/6J (B6) mice fed high-fat diets and B6 ob/ob mice | miR-141-3p | AML12 liver cells | Decreased miR-141-3p expression caused impaired insulin signaling and glucose uptake in the hepatocytes | Exosomes from obese adipose tissues induced hepatocyte insulin resistance | [40] |
| Exosomes | Adipocytes | Human, Females with BMI 51.2±8.8 kg/m2 | MicroRNAs | Insulin receptor signaling pathway | Circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlated with improved post-surgery insulin sensitivity | Bypass surgery intervention changed the properties of the exosomes derived from the adipocyte tissues | [41] |
| Exosomes | Hepatocytes | C57BL/6 mice fed high-fat diets | Sphingosine-1-phosphate (S1P) | BMDM | Hepatocytes EVs with S1P-enriched activated macrophage chemotaxis via the S1P1 receptor | Lipotoxic hepatocytes-derived EVs induce macrophage chemotaxis | [48] |
| Exosomes | Hepatocytes | C56Bl/6J mice fed high-fat diets | Pro-inflammatory lipids (C16:0 ceramide) | Macrophages | Lipotoxic hepatocyte-EVs stimulated macrophage chemotaxis via S1P generation | Lipotoxic hepatocytes-derived EVs induce macrophage chemotaxis | [49] |
| Exosomes | Hepatocytes | C56Bl/6J mice fed high-fat diets | miR-130a-3p | Adipocytes, PHLPP2 | High expression of miR-130a-3p suppressed PHLPP2 expression to activate AKT-AS160–GLUT4 signaling pathway in adipocytes | miR-130a-3p regulates glucose metabolism by increasing glucose uptake | [50] |
| Exosomes | Hepatocytes | Huh7 cells treated with palmitate | MicroRNAs (especially miR-122 and miR-192) | HSCs | Hepatocyte-EVs increased the expression of pro-fibrotic markers such as α-SMA, TGF-β, and COL1A1 in HSCs. | Activation of fibrosis molecules | [51] |
| Microvesicle | Hepatocytes | HepG2 cells treated with palmitate | - | HSCs and hepatocytes | Lipotoxic hepatocyte-microvesicle internalization activated NLRP3 inflammasome via NF-kB, pro-caspase-1 and pro-interleukin-1, IL-1β | Activation of inflammatory phenotype in macrophages | [52] |
| Extracellular vesicles | Adipocytes | Patients with vascular disease | Cystatin-C | Monocytes, endothelial cells, platelets | The elevated level of EVs-cystatin C associated with metabolic complications of obesity | Low HDL cholesterol was significantly related to higher EV-cystatin C levels | [42] |
| Extracellular vesicles | Hepatocytes | C57BL/6 mice with choline-deficient amino acid diet | MicroRNAs (especially miR-128-3p) | HSCs | miR-128-3p suppressed the expression of PPARγ in HSCs | Activation of the HSCs | [53] |
| Extracellular vesicles | Hepatocytes | C57BL/6 mice model of NASH | TRAIL | IL-1β and IL6 in BMDM | Lipotoxic hepatocytes induced releases of pro-inflammatory EVs that activated macrophage via the death receptor 5 (DR5)-dependent manner | Activation of inflammatory phenotype in macrophages due to excess lipids in the liver cells | [11] |
| Extracellular vesicles | Hepatocytes | Primary hepatocytes and Huh7 cells treated with palmitate | CXCL10 | BMDM | Lipotoxic EVs have enriched of CXCL10, a chemotaxis inducer for macrophages | Lipotoxic hepatocytes-EVs activated macrophage chemotaxis | [54] |
| Extracellular vesicles | Hepatocytes, macrophage, neutrophil, platelet | C56BL/6J mice fed high-fat diets | - | Changes in liver condition (onset of NASH) | Quantitative evolution of hepatocyte-, macrophage- and neutrophil-derived EVs correlated well with the histology of NASH | Circulating EVs derived from different cells are enriched at a specific time, according to NASH development | [45] |
| Extracellular vesicles | Serum | C56BL/6J mice fed high-fat diets and underwent aerobic training | MicroRNAs (especially miR-122, miR-192, and miR-22) | Hepatocytes, adipocytes | Serum EVs miR-22 expression was associated with adipogenesis and insulin sensitivity markers in adipocytes. Liver PPARγ expression was negatively correlated with serum miR-122 level | Aerobic training prevented obesity-induced steatohepatitis | [43] |
| Extracellular vesicles | Plasma, hepatocytes | C56BL/6J male mice fed high-fat diets | S1P | BMDM and HSCs | Circulating EVs were enriched in mice with high-fat diets | Activation of inflammatory phenotype in macrophages | [55] |
| Extracellular vesicles | Hepatocytes | C57BL/6J mice fed high-fat diets | MicroRNAs (especially miR-122, let-7e-5p, miR-31-5p and miR-210-3p) | Adipocytes | Increased miR-122, let-7e-5p, miR-31-5p and miR-210-3p expression in adipocytes | Hepatocyte-EVs increased fat accumulation and the expression of lipogenesis genes | [56] |
| Extracellular vesicles | Hepatocytes | HepG2 cells treated with cobalt chloride (CoCl2) or excess fatty acids | - | HSCs | Hepatocyte-EVs increased the expression of the pro-fibrotic markers of TGFβ-1, CTGF, COL1A1, and α-SMA in HSCs | Activation of the fibrosis and HSCs | [57] |
| Extracellular vesicles | Hepatocytes | HepG2 cells treated with cobalt chloride (CoCl2) or excess fatty acids | - | Kupffer cells | Hepatocyte-EVs have enrichment of the pro-inflammatory cytokines and inflammasomes (interleukin-1β, NLRP3, and ASC). Hepatocyte-EVs induced chemotaxis in Kupffer cells | Lipotoxic hepatocytes-EVs activated Kupffer cells chemotaxis | [58] |
| Extracellular vesicles | Hepatocytes | Hepatocytes treated with palmitate | MicroRNAs (especially miR-1) | Human umbilical vein endothelial cells (HUVECs) | miR-1 suppressed expression of KLF-4 and increased the NF-κB activity | Hepatocyte-EVs induced endothelial cell inflammation | [59] |
Abbreviation: Adipose tissue macrophages (ATMs), Alpha-smooth muscle actin (α-SMA), Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), Body Mass Index (BMI), Bone marrow–derived macrophages (BMDM), Connective tissue growth factor (CTGF), C-X-C-motif chemokine 10 (CXCL10), Extracellular matrix (ECM), Extracellular vesicles (EVs), Geranylgeranyl diphosphate synthase (Ggpps), Human umbilical vein endothelial cells (HUVECs), Interleukin-6 (IL-6), Kruppel-like factor 4 (KLF4), Macrophage colony-stimulating factor (MCSF), Matrix metalloproteinase-9 (MMP-9), Non-alcoholic steatohepatitis (NASH), NLR family pyrin domain containing 3 (NLRP3), Nuclear factor kappa B (NF-κB), Peroxisome proliferator-activated receptor delta (PPARD), Peroxisome proliferator-activated receptor gamma (PPARγ), PH Domain And Leucine Rich Repeat Protein Phosphatase 2 (PHLPP2), Retinol binding protein 4 (RBP4), Sphingosine-1-phosphate (S1P), Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), Tissue inhibitor of matrix metalloproteinase-4 (TIMP-4), TNF-related apoptosis-inducing ligand (TRAIL), Transforming growth factor beta (TGF-β), Tumor necrosis factor-alpha (TNF-α), Visceral adipose tissue (VAT).