Role of Extracellular Vesicles in the Pathophysiology, Diagnosis and Tracking of Non-Alcoholic Fatty Liver Disease

Figures

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  Figure 1. Clinical spectrum and progression of non-alcoholic fatty liver disease (NAFLD). Patients may present with simple steatosis due to lipid accumulation in hepatocytes, or non-alcoholic steatohepatitis (NASH), which is characterised by inflammation, hepatocyte death and fibrosis. Fibrosis can progress to cirrhosis and these patients have an increased risk of hepatocellular carcinoma.

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  Figure 2. Signalling pathways leading to apoptotic cell death in lipotoxic hepatocytes. Palmitate and other toxic lipid metabolites trigger ligand-independent activation of TRAIL-R2 (DR5), leading to cell death via caspase 8 and egress of pro-apoptotic factors from the mitochondria. Toxic lipids also contribute to ER stress which may initiate the intrinsic pathway of apoptosis. ER: Endoplasmic reticulum; TRAIL-R2/DR5: TNF-related apoptosis-inducing ligand receptor 2/death receptor 5.

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  Figure 3. Pathways of small extracellular vesicle (sEV) biogenesis and summary of cargo. (A) Intraluminal vesicles (ILVs) are formed by invagination of the early endosomal membrane and subsequently secreted as exosomes. Multivesicular body (MVB) formation may be dependent on tetraspanins and ESCRT machinery or ceramides and trafficking to the membrane involves Rab GTPases. (B) Microvesicles (MVs) are shed directly from the plasma membrane. Various proteins are involved at the site of membrane blebbing and in processing cargo. EV cargo includes nucleic acids, proteins and lipids. ESCRT: endosomal sorting complex required for transport.

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  Figure 4. Lipotoxic hepatocytes release increased numbers of small EVs containing specific cargo that contribute to disease processes in non-alcoholic fatty liver disease. Multiple signalling pathways, including via ER stress sensors, c-Jun N-terminal kinase (JNK) and caspase activation, promote the release of EVs with cargo that promote endothelial cell migration and angiogenesis, transdifferentiation of hepatic stellate cells to a profibrogenic phenotype, macrophage activation and chemotaxis and apoptosis of neighbouring hepatocytes.