Extracellular Vesicles as Inflammatory Drivers in NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease in most parts of the world affecting one-third of the western population and a growing cause for end-stage liver diseases such as hepatocellular carcinoma (HCC). Majorly driven by obesity and diabetes mellitus, NAFLD is more of a multifactorial disease affected by extra-hepatic organ crosstalk. Non-alcoholic fatty liver (NAFL) progressed to non-alcoholic steatohepatitis (NASH) predisposes multiple complications such as fibrosis, cirrhosis, and HCC. Although the complete pathogenic mechanisms of this disease are not understood, inflammation is considered as a key driver to the onset of NASH. Lipotoxicity, inflammatory cytokines, chemokines, and intestinal dysbiosis trigger both hepatic and systemic inflammatory cascades simultaneously activating immune responses. Over a few years, extracellular vesicles studied extensively concerning the pathobiology of NAFLD indicated it as a key modulator in the setting of immune-mediated inflammation. Exosomes and microvesicles, the two main types of extracellular vesicles are secreted by an array of most mammalian cells, which are involved mainly in cell-cell communication that are unique to cell type. Various bioactive cargoes containing extracellular vesicles derived from both hepatic and extrahepatic milieu showed critical implications in driving steatosis to NASH reaffirming inflammation as the primary contributor to the whole process. In this mini-review, we provide brief insights into the inflammatory mediators of NASH with special emphasis on extracellular vesicles that acts as drivers of inflammation in NAFLD.

Enlarged extracellular vesicles are a negative prognostic factor in patients undergoing TACE for primary or secondary liver cancer–a case series

“…In the context of inflammation it was recently demonstrated that miRNA- let-7e-5p, contained in EVs derived from hepatocytes enhances lipid accumulation in adipocytes [ 30 ]. Moreover, EV-miR-192-5p from hepatocytes activate macrophages and increase IL-6 and TNF-α expression, promoting inflammation in NAFLD, summarized in [ 31 ]. Thus, beyond demonstrating a potential role of EV as biomarkers in patients receiving TACE our data also provide pathophysiological insights into different processes determining the prognosis of these patients.…”

Cellular Mechanisms of Liver Fibrosis

“…Administration of EV isolated from high fat diet (HFD) mice into normal fed mice have been shown to result in exacerbation of hepatic steatosis and accumulation of activated myeloid cells in the liver through the release of chemotactic EV ( Ibrahim et al, 2016 ). In addition to hepatocyte-derived EV, extra-hepatic EV have also been implicated in the progression of NAFLD, NASH and associated fibrosis ( Srinivas et al, 2021 ). Due to their ability to carry signal from one cell type to another, they can activate or modulate target cell responses and are therefore an emerging therapeutic targets in NAFLD and NASH.…”

Extracellular Vesicles in Non-alcoholic Fatty Liver Disease and Alcoholic Liver Disease

“…Hepatocytes are the main cell type of the liver, accounting for 80% of the liver volume. Studies on mouse models and human subjects with NASH showed that hepatocytes are the main contributors to the elevated levels of circulating EVs ( Srinivas et al, 2020 ). Therefore, hepatocyte-derived EVs may play a key role in the pathogenesis and progression of NAFLD.…”