Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update
Abstract
:1. Introduction
2. Extracellular Vesicles (EVs): Biogenesis and Classes
2.1. Extracellular Vesicles (EVs): Exosomes
2.2. Extracellular Vesicles (EVs): Microvesicles
2.3. Extracellular Vesicles (EVs): Apoptotic Bodies
3. Extracellular Vesicles (EVs): Adipocyte-Derived EVs in NAFLD
4. Extracellular Vesicles (EVs): Damaged Hepatocytes Roles in NAFLD
5. EVs from the Mesenchymal Stem Cells as a Treatment Option
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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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] |
Extracellular Vesicles | Cell Source | Molecular Mediators in the EVs Cargos | Recipient Targets Model | Interaction | Clinical Relevance | Reference |
---|---|---|---|---|---|---|
Exosomes | Human umbilical cord MSCs (hucMSC) | mRNA, surface adhesion molecules | Acute liver injury mice model (CCl4 treatment) | hucMSC exosomes recovered AST activity, reduced COL1A1, COL3A1, and TGF-β1 expressions | Alleviation of liver fibrosis | [73] |
Exosomes | hucMSC | GPX1 | Acute liver injury mice model (CCl4 treatment) | Reduction of hepatic ROS and apoptosis by increasing the ERK1/2 and BCL-2 and decreasing the IKKB/NFkB/Casp-9/-3 pathway | The recovery of hepatic oxidant injury | [81] |
Exosomes | hucMSC | - | Acute liver injury mice model (LPS and D-galactosamine treatment), RAW264.7 macrophages | Reduction of NLRP3, Casp-1, IL-1β, IL-6 expressions in the macrophage, liver ALT and AST levels, and the restoration of damaged liver tissue | Reduced inflammation and liver damage is repaired | [83] |
Exosome | Chorionic plate-derived MSCs (CP-MSCs) | miR-125b | Acute liver injury mice model (CCl4 treatment), hepatic stellate cells (HSCs) | miR-125b suppressed the activation of Hh signaling that promotes fibrosis | Suppression of the HSCs activation and proliferation | [92] |
Exosomes | MSCs | - | Acute liver injury mice model (CCl4 treatment), hepatocytes | MSCs exosomes activated proliferation genes and prevented apoptosis | MSC-derived exosomes have hepatoprotective effects against acute-liver injury | [74] |
Exosomes | Adipose tissue-derived MSCs (AMSCs) | miR-17 | Acute liver injury mice model (LPS and D-galactosamine treatment), Kupffer cells | miR-17 reduced TXNIP expression and suppressed the NLRP3 inflammasome activation in Kupffer cells | Reduction of inflammatory activation in Kupffer cells | [89] |
Exosomes | AMSCs | miR-181-5p | Acute liver injury mice model (CCl4 treatment), HSCs | miR-181-5p increased autophagy and reduced liver fibrosis by inhibiting the STAT3/BCL-2/Beclin-1 pathway HSCs COL1A1, VIMENTIN, α-SMA, and FN1 expressions were reduced | AMSCs exosomal miR-181-5p has an anti-fibrotic role | [93] |
Exosomes | AMSCs | miR-122 | Acute liver injury mice model (CCl4 treatment), HSCs | miR-122 reduced the expression of IGF1R, CCNG1, and P4HA1 in HSCs | Suppression of the HSCs proliferation and collagen maturation | [94] |
Exosome | Adipose-derived stem cells (ADSC) | STAT3 | Mice fed high-fat diets, macrophages | ADSC exosomes improved insulin sensitivity, reduced obesity, and alleviated hepatic steatosis, by inducing the anti-inflammatory phenotypes in M2 macrophages via the transactivation of arginase-1 by exosome-STAT3 | Improvement of insulin regulation and hepatic steatosis | [72] |
Exosomes | Bone-marrow-derived MSC (BMSCs) | - | Acute liver injury mice model (CCl4 treatment), hepatocytes (Acetaminophen or hydrogen peroxide treatment) | Reduced ROS production and prevented oxidative stress, as well as improved liver regeneration and recovery | The recovery of hepatic oxidant injury | [76] |
Exosomes | BMSCs | - | Hepatocytes (LPS and D-galactosamine treatment) | BMSCs exosomes reduced the pro-apoptotic proteins BAX, and cleaved Casp-3, and increased the expression of the anti-apoptotic BCL-2 | Induce autophagy and protect hepatic cells from damage caused by various stresses by mediating autophagy | [80] |
Exosome | BMSCs | - | Acute liver injury mice model (CCl4 treatment), HSCs | BMSCs exosomes alleviated liver fibrosis and inflammation, as well as reduced the expression of Wnt/β-catenin pathway components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, CCND1, α-SMA, and COL1A1) in HSCs and liver tissue | Alleviation of liver fibrosis via the inhibition of Wnt/β-catenin signaling | [79] |
Exosomes | Human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) | - | Liver injury mice model (ischemia/reperfusion surgery), hepatocytes | hiPSC-MSCs exosomes reduced AST and ALT levels and increased primary hepatocyte proliferation and synthesis of S1P | Protection against hepatic ischemia/reperfusion injury | [86] |
Exosomes | Human menstrual blood-derived stem cells (MenSCs) | ICAM-1, angiopoietin-2, Axl, angiogenin, IGFBP-6, osteoprotegerin, IL-6, and IL-8 | Acute liver injury mice model (LPS and D-galactosamine treatment), AML12 macrophage cells | MenSCs exosomes improved liver function and inhibited apoptosis with a reduction of active Casp-3 | Inhibition of cell apoptosis and enhanced survival | [87] |
Microvesicles (MVs) | Human liver stem cells (HLSC) | mRNAs | Hepatocytes | HLSC MVs activated cell proliferation and liver regeneration | Liver regeneration | [84] |
Extracellular vesicles | HLSC | ASS1 protein and mRNA | Hepatocytes derived from ASS1 deficient HLSC | HLSC EVs restored ASS1 activity and urea production | Restoration of ASS1 function in deficient cells | [85] |
Extracellular vesicles | HLSC | NASH mice model (choline-deficient amino acid diet) | HLSC EVs reduced fibrosis and inflammation markers (α-SMA), COL1A1, TGF-β1, TNF-α, IL-1β, and LTBP1 | Reduction of inflammation and fibrogenesis | [98] | |
Extracellular vesicles | hucMSC | MnSOD enzyme | Liver injury mice model (ischemia/reperfusion surgery) | hucMSC EVs reduced neutrophils infiltration and alleviated hepatic oxidative stress | Inhibition of the oxidative stress and neutrophil inflammatory response | [82] |
Extracellular vesicles | hucMSC | - | Liver injury mice model (S. japonicum infection), HSCs | hUCMSC EVs ameliorated liver injury and reduced the expression of α-SMA, COL1A1, and COL3A1, as well as HSCs proliferation | Suppression of HSCs proliferation and improved liver condition | [99] |
Extracellular vesicles | Amnion-derived mesenchymal stem | - | NASH mice model (high-fat diets), Acute liver injury mice model (CCl4 treatment), HSCs and Kupffer cells | AMSC EVs reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and TGF-β), fibrosis, Kupffer cell numbers, and HSC activation | Reduction of inflammation and fibrogenesis | [97] |
Extracellular vesicles | BMSCs | Y-RNA-1 | Liver failure mice model (D-galactosamine/TNF-α treatment), hepatocytes | BMSCs EVs reduced hepatic injury and apoptosis | Protective effect against hepatocyte apoptosis | [75] |
Extracellular vesicles | BMSCs | - | Liver injury mice model (ischemia/reperfusion surgery), hepatocytes | BMSCs EVs reduced tissue necrosis, apoptosis, serum ALT, and increased expression of NLRP12 and CXCL1, as well as increased the expression of IL-6 | Reduction of tissue necrosis, inflammation, and apoptosis | [77] |
Extracellular vesicles | Human mesenchymal stromal cell (hMSCs) | - | Liver injury mice model (ischemia/reperfusion surgery) | hMSCs EVs reduced hepatic necrosis and inflammatory genes (HMBG-1, ICAM-1, HO-1, and IL-1β) | Reduction of tissue necrosis and inflammation | [78] |
Extracellular vesicles | Human embryonic stem cell-derived mesenchymal stroma cells | - | Liver injury mice model (thioacetamide treatment) | EVs reduced fibrosis, apoptosis, and regenerated liver cells | Regeneration of liver | [64] |
Extracellular vesicles | Human adipose-derived stem cells (hASCs) | lncRNA H19 | Acute liver injury mice model (D-galactosamine treatment) | hASCs EVs reduced the expression of inflammatory mediators and chemotactic factors | Inhibition of the liver inflammation | [90] |
Extracellular vesicles | hASCs | - | NASH mice model (high-fat diets) with acute liver injury (LPS treatment) | hASCs EVs reduced serum ALT levels and inflammatory markers and macrophages | Inhibition of the liver inflammation | [95] |
Extracellular vesicles | Human induced pluripotent stem cell (iPSCs) | MicroRNAs (specifically miR-92a-3p) | HSCs | iPSCs EVs reduced pro-fibrogenic markers (α–SMA, COL1A1, FN1, and TIMP-1), and HSC proliferation | Inhibition of fibrosis and HSCs proliferation | [96] |
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Dorairaj, V.; Sulaiman, S.A.; Abu, N.; Abdul Murad, N.A. Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update. Biomolecules 2020, 10, 1494. https://doi.org/10.3390/biom10111494
Dorairaj V, Sulaiman SA, Abu N, Abdul Murad NA. Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update. Biomolecules. 2020; 10(11):1494. https://doi.org/10.3390/biom10111494
Chicago/Turabian StyleDorairaj, Vicneswarry, Siti Aishah Sulaiman, Nadiah Abu, and Nor Azian Abdul Murad. 2020. "Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update" Biomolecules 10, no. 11: 1494. https://doi.org/10.3390/biom10111494