Diabetes Metab J.  2016 Feb;40(1):1-11. 10.4093/dmj.2016.40.1.1.

Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis

• Povero D
• Feldstein

• KMID: 2383309
• DOI: http://doi.org/10.4093/dmj.2016.40.1.1

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH). A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis), which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs) have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease.

Keyword

Angiogenesis; Cell death; Cirrhosis; Extracellular vesicles; Lipotoxicity

MeSH Terms

Adult
Cell Death
Child
Diagnosis
Fatty Liver*
Fibrosis
Genetics
Hepatocytes
Humans
Inflammation
Liver
Liver Cirrhosis
Liver Diseases
Microbiota
Neovascularization, Pathologic

Figure

• 

  Fig. 1 Extracellular vesicles at play. Extracellular vesicles (EVs) or exovesicles are membrane surrounded structures release by cells both during physiological as well as under various stress conditions and they can be divided into exosomes, ectosomes, or microparticles, and apoptotic bodies. Exosomes (30 to 100 nm) are released via exocytosis through the fusion of multivesicular bodies (MVB) with plasma membranes. Ectosomes are vesicles 100 to 1,000 nm in size and they are released by direct blebbing/budding from the plasma membrane. Apoptotic bodies are released by fragmentation of a cell during programmed cell death. Exovesicles express several cell specific and stress specific markers and carry a variety of bioactive molecules, including non-coding long and micro-RNAs, mRNA, lipids, and proteins. TSG101, tumor susceptibility gene 101.

• 

  Fig. 2 Extracellular vesicles in the pathogenesis of fatty liver disease. During the process of lipotoxicity, hepatocytes release large quantities of extracellular vesicles (EVs) that may then act on various target cells in the local environment they are released contributing to key processes involved in non-alcoholic fatty liver disease pathogenesis including immune modulation, angiogenesis, and fibrosis. Additionally, EVs may be released to the systemic circulation and can be potentially used to non-invasively monitoring the extent of liver injury.

• 

  Fig. 3 Hepatocyte-derived extracellular vesicles released during lipotoxicity and their role in liver fibrosis and inflammation. Lipid-induced toxicity (lipotoxicity) due to over-accumulation of various toxic lipids in hepatocytes such as saturated free fatty acids induce the release of exovesicles in a process that may involved activation of caspases such as caspase-3 as well as stress-activated kinases such MLK3, ROCK1. Liver-derived exovesicles carry several bioactive molecules (e.g., CXCL10, connective tissue growth factor, Twist1) and non-coding small or long RNAs, such as miR-128. These signals are shuttled by exovesicles and can modulate inflammation and fibrogenesis by recruiting or activating macrophages and quiescent hepatic stellate cells (HSCs), respectively. Notably, anti-fibrotic factors can be also transferred into extracellular vesicles and lead to HSC inactivation. CXCL10, chemokine (C-X-C motif) ligand 10; MLK3, mixed lineage kinase 3; ROCK, Rho-associated coiled-coil-containing protein kinase 1; CCN, connective tissue growth factor.

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