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Extracellular vesicles nash

Akiko Eguchi, Ariel E Feldstein
Fatty liver diseases, non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common causes of chronic liver disease around the world. NAFLD and ALD can progress towards a more severe form of the disease, including as non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH). In both instances central pathogenic events include hepatocyte death, liver inflammation, pathological angiogenesis, and fibrosis, followed by cirrhosis and cancer. Over the last few years, extracellular vesicles (EVs) have been identified as effective cell-to-cell communicators that contain a cell- and stress-specific cargo from the cell of origin and are capable of transferring this cargo to a target or acceptor cell...
March 2018: Liver Research
Sahithi J Kuravi, Paul Harrison, George Ed Rainger, Gerard B Nash
We tested the ability of platelet-derived extracellular vesicles (PEV) to promote adhesion of flowing neutrophils to endothelial cells (EC). PEV were collected from platelets stimulated with collagen-related peptide, and differential centrifugation was used to collect larger vesicles enriched for platelet membrane microvesicles (PMV) or smaller vesicles enriched for platelet exosomes (Pexo). Vesicle binding and resultant activation of neutrophils and EC were assessed by flow cytometry. Flow-based adhesion assays assessed binding of neutrophils directly to deposited vesicles or to EC, after neutrophils or EC had been treated with vesicles...
September 14, 2018: Inflammation
Geoffrey C Farrell, Fahrettin Haczeyni, Shivakumar Chitturi
Overnutrition, usually with obesity and genetic predisposition, lead to insulin resistance, which is an invariable accompaniment of nonalcoholic fatty liver disease (NAFLD). The associated metabolic abnormalities, pre- or established diabetes, hypertension and atherogenic dyslipidemia (clustered as metabolic syndrome) tend to be worse for nonalcoholic steatohepatitis (NASH), revealing it as part of a continuum of metabolic pathogenesis. The origins of hepatocellular injury and lobular inflammation which distinguish NASH from simple steatosis have intrigued investigators, but it is now widely accepted that NASH results from liver lipotoxicity...
2018: Advances in Experimental Medicine and Biology
Junfa Yang, Changyao Li, Lei Zhang, Xiao Wang
Extracellular vesicles (EVs) are small membranous vesicles secreted from normal, diseased, and transformed cells in vitro and in vivo . EVs have been found to play a critical role in cell-to-cell communication by transferring non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long ncRNAs (lncRNAs) and so on. Emerging evidence shows that transferring biological information through EVs to neighboring cells in intercellular communication not only keep physiological functions, but also participate in the pathogenesis of liver diseases...
2018: Frontiers in Pharmacology
Yun Qiu, Sufan Wang, Ting Wan, Mingtong Ye, Rui Jiang, Lei Pei, Lili Yang
Nonalcoholic fatty liver disease has become a social health challenge of global concern. The term nonalcoholic steatohepatitis (NASH) is a more severe condition than simple steatosis and distinguishing NASH from nonalcoholic fatty liver disease is particularly important. Liver biopsy remains a gold standard in diagnosing NASH. Meanwhile, radiological techniques such as ultrasonography and MRI are also applied widely. However, the invasive and expensive examination is not suitable for screening, and there is a great need for reliable and appropriate biomarkers to screen patients for NASH...
May 2018: Biomarkers in Medicine
Samar H Ibrahim, Petra Hirsova, Gregory J Gores
A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed non-alcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH...
May 2018: Gut
Sahithi J Kuravi, Clara M Yates, Mark Foster, Paul Harrison, Jon Hazeldine, Peter Hampson, Chris Watson, Antonio Belli, Mark Midwinter, Gerard B Nash
BACKGROUND: Extracellular vesicles (EV) released into the circulation after traumatic injury may influence complications. We thus evaluated the numbers of EV in plasma over 28 days after trauma and evaluated their pro-coagulant and inflammatory effects. METHODS AND FINDINGS: 37 patients suffering trauma with an injury severity score >15 were studied along with 24 healthy controls. Plasma samples were isolated by double centrifugation (2000g 20min; 13000g 2min) from blood collected from within an hour up to 28 days after injury...
2017: PloS One
Kyoko Tomita, Ayano Kabashima, Brittany L Freeman, Steven F Bronk, Petra Hirsova, Samar H Ibrahim
Saturated fatty acids (SFA) and their toxic metabolites contribute to hepatocyte lipotoxicity in nonalcoholic steatohepatitis (NASH). We previously reported that hepatocytes, under lipotoxic stress, express the potent macrophage chemotactic ligand C-X-C motif chemokine 10 (CXCL10), and release CXCL10-enriched extracellular vesicles (EV) by a mixed lineage kinase (MLK) 3-dependent mechanism. In the current study, we sought to examine the signaling pathway responsible for CXCL10 induction during hepatocyte lipotoxicity...
October 2017: Journal of Cellular Biochemistry
Amy S Mauer, Petra Hirsova, Jessica L Maiers, Vijay H Shah, Harmeet Malhi
Nonalcoholic steatohepatitis (NASH) is a lipotoxic disorder, wherein proinflammatory lipids, such as ceramide and its derivative sphingosine 1-phosphate (S1P), contribute to macrophage-associated liver inflammation. For example, we have previously demonstrated a role for S1P in steatotic hepatocyte-derived S1P-enriched extracellular vesicles in macrophage chemotaxis in vitro. Therefore, we hypothesized that FTY720, an S1P antagonist, would ameliorate NASH by inhibiting proinflammatory monocyte chemotaxis. To test our hypothesis, NASH was established in C57BL/6 male mice by feeding a diet high in fructose, saturated fat, and cholesterol for 22 wk...
March 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
Kyoko Tomita, Brittany L Freeman, Steven F Bronk, Nathan K LeBrasseur, Thomas A White, Petra Hirsova, Samar H Ibrahim
Nonalcoholic steatohepatitis (NASH) is an inflammatory lipotoxic disorder, but how inflammatory cells are recruited and activated within the liver is still unclear. We previously reported that lipotoxic hepatocytes release CXCL10-enriched extracellular vesicles, which are potently chemotactic for cells of the innate immune system. In the present study, we sought to determine the innate immune cell involved in the inflammatory response in murine NASH and the extent to which inhibition of the chemotactic ligand CXCL10 and its cognate receptor CXCR3 could attenuate liver inflammation, injury and fibrosis...
June 28, 2016: Scientific Reports
Petra Hirsova, Samar H Ibrahim, Gregory J Gores, Harmeet Malhi
The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops progressive liver disease, termed nonalcoholic steatohepatitis, which is characterized by hepatocellular apoptosis and innate immune system-mediated inflammation. These responses are orchestrated by signaling pathways that can be activated by lipids, directly or indirectly. In this review, we discuss palmitate- and lysophosphatidylcholine (LPC)-induced upregulation of p53-upregulated modulator of apoptosis and cell-surface expression of the death receptor TNF-related apoptosis-inducing ligand receptor 2...
October 2016: Journal of Lipid Research
Davide Povero, Ariel E Feldstein
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...
February 2016: Diabetes & Metabolism Journal
Petra Hirsova, Samar H Ibrahim, Anuradha Krishnan, Vikas K Verma, Steven F Bronk, Nathan W Werneburg, Michael R Charlton, Vijay H Shah, Harmeet Malhi, Gregory J Gores
BACKGROUND & AIMS: Hepatocyte cellular dysfunction and death induced by lipids and macrophage-associated inflammation are characteristics of nonalcoholic steatohepatitis (NASH). The fatty acid palmitate can activate death receptor 5 (DR5) on hepatocytes, leading to their death, but little is known about how this process contributes to macrophage-associated inflammation. We investigated whether lipid-induced DR5 signaling results in the release of extracellular vesicles (EVs) from hepatocytes, and whether these can induce an inflammatory macrophage phenotype...
April 2016: Gastroenterology
Eiji Kakazu, Amy S Mauer, Meng Yin, Harmeet Malhi
Nonalcoholic steatohepatitis (NASH) is a lipotoxic disease wherein activation of endoplasmic reticulum (ER) stress response and macrophage-mediated hepatic inflammation are key pathogenic features. However, the lipid mediators linking these two observations remain elusive. We postulated that ER stress-regulated release of pro-inflammatory extracellular vesicles (EVs) from lipotoxic hepatocytes may be this link. EVs were isolated from cell culture supernatants of hepatocytes treated with palmitate (PA) to induce lipotoxic ER stress, characterized by immunofluorescence, Western blotting, electron microscopy, and nanoparticle tracking analysis...
February 2016: Journal of Lipid Research
Samar H Ibrahim, Petra Hirsova, Kyoko Tomita, Steven F Bronk, Nathan W Werneburg, Stephen A Harrison, Val S Goodfellow, Harmeet Malhi, Gregory J Gores
UNLABELLED: Mixed lineage kinase 3 (MLK3) deficiency reduces macrophage-associated inflammation in a murine model of nonalcoholic steatohepatitis (NASH). However, the mechanistic links between MLK3 activation in hepatocytes and macrophage-driven inflammation in NASH are uncharted. Herein, we report that MLK3 mediates the release of (C-X-C motif) ligand 10 (CXCL10)-laden extracellular vesicles (EVs) from lipotoxic hepatocytes, which induce macrophage chemotaxis. Primary mouse hepatocytes (PMHs) and Huh7 cells were treated with palmitate or lysophosphatidylcholine (LPC)...
March 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Petra Hirsova, Gregory J Gores
Nonalcoholic fatty liver disease (NAFLD) is becoming public health problem worldwide. A subset of patients develop an inflammatory disease, nonalcoholic steatohepatitis (NASH), characterized by steatosis, hepatocellular death, macrophage and neutrophil accumulation and varying stages of fibrosis. Hepatocyte cell death triggers the cellular inflammatory response and, therefore, reducing cell death may be salutary in the steatohepatitis disease process. Recently, a better understanding of hepatocyte apoptosis in NASH has been obtained and new information regarding other cell death modes, such as necroptosis and pyroptosis, has been reported...
January 2015: Cellular and Molecular Gastroenterology and Hepatology
María C Touz, Natalia Gottig, Theodore E Nash, Hugo D Lujan
Giardia lamblia is a flagellate protozoan that infects humans and other mammals and the most frequently isolated intestinal parasite worldwide. Giardia trophozoites undergo essential biological changes to survive outside the intestine of their host by differentiating into infective cysts. Cyst formation, or encystation, is considered one of the most primitive adaptive responses developed by eukaryotes early in evolution and crucial for the transmission of the parasite among susceptible hosts. During this process, proteins that will assemble into the extracellular cyst wall (CWP1 and CWP2) are transported to the cell surface within encystation-specific secretory vesicles (ESVs) by a developmentally regulated secretory pathway...
December 27, 2002: Journal of Biological Chemistry
María C Touz, María J Nores, Ileana Slavin, Carlos Carmona, John T Conrad, Michael R Mowatt, Theodore E Nash, Carlos E Coronel, Hugo D Luján
Giardia is an intestinal parasite that belongs to the earliest diverging branch of the eukaryotic lineage of descent. Giardia undergoes adaptation for survival outside the host's intestine by differentiating into infective cysts. Encystation involves the synthesis and transport of cyst wall constituents to the plasma membrane for release and extracellular organization. Nevertheless, little is known about the molecular events related to cyst wall biogenesis in Giardia. Among the components of the cyst wall there are two proteins that we have previously identified and characterized: CWP1 (26 kDa) and CWP2 (39 kDa)...
March 8, 2002: Journal of Biological Chemistry
T C Nash, M J Buchmeier
OBLV60 is an acid-dependent syncytium-forming variant isolated from OBL21 cells persistently infected with the pH-independent mouse hepatitis virus (MHV)-4 strain. The fusion activity of OBLV60 can be strictly regulated by controlling pH and thus provides the means to definitively examine the entry of MHV into cells by endosomal and nonendosomal pathways. Shortly after high multiplicity infection, both MHV-4 and OBLV60 were detected by electron microscopy in endosomal vesicles and were recovered from lysates of cells treated with proteinase K to remove extracellular virus...
June 23, 1997: Virology
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