scholarly journals Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

Gut ◽  
2018 ◽  
Vol 67 (5) ◽  
pp. 963-972 ◽  
Author(s):  
Samar H Ibrahim ◽  
Petra Hirsova ◽  
Gregory J Gores
Keyword(s):  
Immune Cell ◽  
Innate Immune ◽  
Liver Inflammation ◽  
Hepatocellular Injury ◽  
Alcoholic Fatty Liver ◽  
Disease Biomarkers ◽  
Alcoholic Steatohepatitis ◽  
Hepatocyte Injury ◽  
Alcoholic Fatty Liver Disease

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. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.

scholarly journals Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 184
Author(s):  
Daryl Ramai ◽  
Waqqas Tai ◽  
Michelle Rivera ◽  
Antonio Facciorusso ◽  
Nicola Tartaglia ◽  
...  
Keyword(s):  
Public Health ◽  
Hepatocellular Carcinoma ◽  
Lipid Peroxidation ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Natural Progression ◽  
Public Health Threat ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.

scholarly journals The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Biology ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 93 ◽  
Author(s):  
Seul Lee ◽  
Dong-Cheol Woo ◽  
Jeeheon Kang ◽  
Moonjin Ra ◽  
Ki Hyun Kim ◽  
...  
Keyword(s):  
Liver Disease ◽  
Epigenetic Modification ◽  
Treatment Options ◽  
Histone Methyltransferase ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Promising Therapeutic Target ◽  
Alcoholic Fatty Liver Disease ◽  
Potential Therapeutics

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

scholarly journals Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

2020 ◽  
Vol 11 ◽  
Author(s):  
Carmelo Luci ◽  
Manon Bourinet ◽  
Pierre S. Leclère ◽  
Rodolphe Anty ◽  
Philippe Gual
Keyword(s):  
Endothelial Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Liver Sinusoidal Endothelial Cells ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Alcoholic Fatty Liver Disease

Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.

scholarly journals Hepatic lymphocytes involved in the pathogenesis of pediatric and adult non-alcoholic fatty liver disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Victoria Cairoli ◽  
Elena De Matteo ◽  
Daniela Rios ◽  
Carol Lezama ◽  
Marcela Galoppo ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Cell ◽  
Age Groups ◽  
Similar Proportion ◽  
Alcoholic Fatty Liver ◽  
T Helper Lymphocytes ◽  
Regulatory T Lymphocytes ◽  
Alcoholic Fatty Liver Disease ◽  
Cd4 Lymphocytes

AbstractThe immune response is critical in NAFLD pathogenesis, but the liver infiltrate’s composition and the role of each T cell population is still up for debate. To characterize liver pathogenesis in pediatric and adult cases, frequency and localization of immune cell populations [Cytotoxic T Lymphocytes (CD8+), T helper Lymphocytes (CD4+), Regulatory T lymphocytes (Foxp3+) and Th17 (IL-17A+)] were evaluated. In portal/periportal (P/P) tracts, both age groups displayed a similar proportion of CD8+ and CD4+ lymphocytes. However, comparable Foxp3+ and IL-17A+ cell frequencies were observed in pediatric cases, meanwhile, in adults Foxp3+ was higher than IL-17A+ cells. Interestingly, IL-17A+ lymphocytes seemed to be nearly exclusive of P/P area in both age groups. In intralobular areas, both pediatric and adult cases showed CD8+ lymphocytes predominance with lower frequencies of CD4+ lymphocytes followed by Foxp3+ . Severe inflammation was associated with higher intralobular Foxp3+ lymphocytes (p = 0.026) in children, and lower P/P Foxp3+ and higher IL-17A+ lymphocytes in adults. All cases with fibrosis ≥ 2 displayed P/P low Foxp3+ and high IL-17A+ lymphocyte counts. Pediatric cases with worse steatosis showed high P/P CD4+ (p = 0.023) and intralobular CD8+ (p = 0.027) and CD4+ cells (p = 0.012). In NAFLD cases, the lymphocyte liver infiltrate composition differs between histological areas. Treg and Th17 balance seems to condition damage progression, denoting their important role in pathogenesis.

scholarly journals Intestinal Dysbiosis and Non-Alcoholic Fatty Liver Disease

2021 ◽  
Author(s):  
Teresa Auguet ◽  
Laia Bertran ◽  
Jessica Binetti
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Immune Cell ◽  
Specific Treatment ◽  
Short Chain Fatty Acids ◽  
Hepatocellular Injury ◽  
Alcoholic Fatty Liver ◽  
Intestinal Dysbiosis ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) affects 20–30% of the population, with an increased prevalence in industrialized regions. Some patients with NAFLD develop an inflammatory condition termed non-alcoholic steatohepatitis (NASH) that is characterized by hepatocellular injury, innate immune cell-mediated inflammation, and progressive liver fibrosis. In clinical practice, abdominal imaging, which reveals hepatic steatosis, is sufficient for NAFLD diagnosis if other diseases have been rejected. However, a liver biopsy is needed to differentiate NASH from simple steatosis. Therapeutic strategies used to treat obesity and metabolic syndrome improve NAFLD, but there is no specific treatment effective for NASH. The gut microbiota (GM) is composed of millions of microorganisms. Changes in the GM have a significant impact on host health. Intestinal dysbiosis is an imbalance in the GM that can induce increased permeability of the epithelial barrier, with migration of GM-derived mediators through portal vein to the liver. These mediators, such as lipopolysaccharides, short-chain fatty acids, bile acids (BAs), choline, and endogenous ethanol, seem to be involved in NAFLD pathogenesis. Given this evidence, it would be interesting to consider GM-derived mediator determination through omics techniques as a noninvasive diagnostic tool for NASH and to focus research on microbiota modulation as a possible treatment for NASH.

Processes exacerbating apoptosis in non-alcoholic steatohepatitis

2019 ◽  
Vol 133 (22) ◽  
pp. 2245-2264 ◽  
Author(s):  
Marta B. Afonso ◽  
Rui E. Castro ◽  
Cecília M. P. Rodrigues
Keyword(s):  
Molecular Mechanisms ◽  
Health Concern ◽  
Alcoholic Fatty Liver ◽  
Intrinsic Signals ◽  
Alcoholic Steatohepatitis ◽  
Significant Public Health Concern ◽  
High Prevalence ◽  
Significant Public Health ◽  
Alcoholic Fatty Liver Disease

Abstract Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern, owing to its high prevalence, progressive nature and lack of effective medical therapies. NAFLD is a complex and multifactorial disease involving the progressive and concerted action of factors that contribute to the development of liver inflammation and eventually fibrosis. Here, we summarize fundamental molecular mechanisms underlying the pathogenesis of non-alcoholic steatohepatitis (NASH), how they are interrelated and possible translation to clinical applications. We focus on processes triggering and exacerbating apoptotic signalling in the liver of NAFLD patients and their metabolic and pathological implications. Indeed, liver injury and inflammation are cardinal histopathological features of NASH, a duo in which derailment of apoptosis is of paramount importance. In turn, the liver houses a very high number of mitochondria, crucial metabolic unifiers of both extrinsic and intrinsic signals that converge in apoptosis activation. The role of lifestyle options is also dissected, highlighting the management of modifiable risk factors, such as obesity and harmful alcohol consumption, influencing apoptosis signalling in the liver and ultimately NAFLD progression. Integrating NAFLD-associated pathologic mechanisms in the cell death context could provide clues for a more profound understating of the disease and pave the way for novel rational therapies.

Bacterial and eukaryotic extracellular vesicles and non-alcoholic fatty liver disease: new players in the gut-liver axis?

2021 ◽  
Author(s):  
Alexandre Villard ◽  
Jérôme Boursier ◽  
Ramaroson Andriantsitohaina
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Extracellular Vesicles ◽  
Fatty Liver Disease ◽  
Chronic Liver ◽  
Present Review ◽  
Liver Inflammation ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

The liver and intestine communicate in a bi-directional way through the biliary tract, portal vein, and other components of the gut-liver axis. The gut microbiota is one of the major contributors to the production of several proteins and bile acids. Imbalance in the gut bacterial community, called dysbiosis, participates in the development and progression of several chronic liver diseases, such as non-alcoholic fatty liver disease (NAFLD). NAFLD is currently considered the main chronic liver disease worldwide. Dysbiosis contributes to NAFLD development and progression, notably by a greater translocation of pathogen-associated molecular patterns (PAMPs) in the blood. Lipopolysaccharide (LPS) is a PAMP that activates toll-like receptor 4 (TLR4), induces liver inflammation, and participates in the development of fibrogenesis. LPS can be transported by bacterial extracellular vesicles (EVs). EVs are spherical structures produced by eukaryotic and prokaryotic cells that transfer information to distant cells and may represent new players in NAFLD development and progression. The present review summarizes the role of eukaryotic EVs, either circulating or tissue-derived, in NAFLD features, such as liver inflammation, angiogenesis, and fibrosis. Circulating EV levels are dynamic and correlate with disease stage and severity. However, scarce information is available concerning the involvement of bacterial EVs in liver disease. The present review highlights a potential role of bacterial EVs in insulin resistance and liver inflammation, although the mechanism involved has not been elucidated. Additionally, because of their distinct signatures, eukaryotic and prokaryotic EVs may also represent a promising NAFLD diagnostic tool as a "liquid biopsy" in the future.

scholarly journals Steroid-mediated liver steatosis is CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes are CD1d-independent: A dichotomy between steatosis and steatohepatitis

2021 ◽  
Author(s):  
Tomer Adar ◽  
Ami Ben Ya'acov ◽  
Shabat Shabat ◽  
Meir Mizrahi ◽  
Lida Zolotarov ◽  
...  
Keyword(s):  
Liver Damage ◽  
Liver Steatosis ◽  
Metabolic Changes ◽  
Liver Necrosis ◽  
Hepatocellular Injury ◽  
Metabolic Derangement ◽  
Alcoholic Fatty Liver ◽  
Killer T Cells ◽  
Alcoholic Fatty Liver Disease

Abstract Glucocorticoids have been implicated in the pathogenesis of all stages of non-alcoholic fatty liver disease (NAFLD). Natural killer T cells play a role in the pathogenesis of NAFLD and in the response to steroids. The aim of the present study was to determine the role of CD1d in steroid-mediated metabolic derangement and the steroid-protective effect of glycosphingolipids. Methods: Ten groups of mice were studied. Steroids were orally administered to C57BL/6 mice to assess the therapeutic effect of β-glucsylceramide (GC) on the development of steroid-mediated liver damage and metabolic derangements. The role of CD1d in the pathogenesis of steroid-induced liver damage, and in mediating the hepatoprotective effect of GC were studied in CD1d−/− mice. Results: A model of oral administration of steroids was established, resulting in insulin resistance, hyperinsulinemia, hypertriglyceridemia, liver steatosis, and hepatocellular injury. Steroid administration to CD1d−/− mice was associated with hyperglycemia and hypertriglyceridemia. However, CD1d−/− mice were relatively resistant to steroid-induced steatosis. GC treatment alleviated steroid-associated metabolic derangements and liver injury independent of CD1d expression. Conclusion: A steroid-mediated model of NAFLD and metabolic derangements was established in which steroid-mediated steatosis was CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes were CD1d-independent, further supporting a dichotomy between steatosis and steatohepatitis in NAFLD.

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