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.

scholarly journals From Liver Fat to Cancer: Perils of the Western Diet

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1095
Author(s):  
Ju Youn Kim ◽  
Feng He ◽  
Michael Karin
Keyword(s):  
Fatty Liver Disease ◽  
Primary Liver Cancer ◽  
Liver Steatosis ◽  
Common Type ◽  
Liver Fat ◽  
Chronic Liver Injury ◽  
Alcoholic Fatty Liver ◽  
Obesity Epidemic ◽  
Alcoholic Fatty Liver Disease

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer provides the prototypical example of an obesity-related cancer. The obesity epidemic gave rise to an enormous increase in the incidence of non-alcoholic fatty liver disease (NAFLD), a condition that affects one third of American adults. In about 20% of these individuals, simple liver steatosis (hepatosteatosis) progresses to non-alcoholic steatohepatitis (NASH) characterized by chronic liver injury, inflammation, and fibrosis. In addition to liver failure, NASH greatly increases the risk of HCC. Here we discuss the metabolic processes that control the progression from NAFLD to NASH and from NASH to HCC, with a special emphasis on the role of free-non-esterified cholesterol in the process.

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 The role of bacterial metabolites derived from aromatic amino acids in non-alcoholic fatty liver disease

2020 ◽  
Vol 48 (6) ◽  
pp. 375-386
Author(s):  
E. S. Shcherbakova ◽  
T. S. Sall ◽  
S. I. Sitkin ◽  
T. Ya. Vakhitov ◽  
E. V. Demyanova
Keyword(s):  
Amino Acids ◽  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver Disease ◽  
Liver Steatosis ◽  
Aromatic Amino Acids ◽  
Microbial Metabolites ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

The review deals with the role of aromatic amino acids and their microbial metabolites in the development and progression of non-alcoholic fatty liver disease (NAFLD). Pathological changes typical for NAFLD, as well as abnormal composition and/or functional activity of gut microbiota, results in abnormal aromatic amino acid metabolism. The authors discuss the potential of these amino acids and their bacterial metabolites to produce both negative and positive impact on the main steps of NAFLD pathophysiology, such as lipogenesis and inflammation, as well as on the liver functions through regulation of the intestinal barrier and microbiota-gut-liver axis signaling. The review gives detailed description of the mechanism of biological activity of tryptophan and its derivatives (indole, tryptamine, indole-lactic, indole-propyonic, indole-acetic acids, and indole-3-aldehyde) through the activation of aryl hydrocarbon receptor (AhR), preventing the development of liver steatosis. Bacteria-produced phenyl-alanine metabolites could promote liver steatosis (phenyl acetic and phenyl lactic acids) or, on the contrary, could reduce liver inflammation and increase insulin sensitivity (phenyl propionic acid). Tyramine, para-cumarate, 4-hydroxyphenylacetic acids, being by-products of bacterial catabolism of tyrosine, can prevent NAFLD, whereas para-cresol and phenol accelerate the progression of NAFLD by damaging the barrier properties of intestinal epithelium. Abnormalities in bacterial catabolism of tyrosine, leading to its excess, stimulate fatty acid synthesis and promote lipid infiltration of the liver. The authors emphasize a close interplay between bacterial metabolism of aromatic amino acids by gut microbiota and the functioning of the human body. They hypothesize that microbial metabolites of aromatic amino acids may represent not only therapeutic targets or non-invasive biomarkers, but also serve as bioactive agents for NAFLD treatment and prevention.

scholarly journals The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 10 (5) ◽  
pp. 1081
Author(s):  
Mikkel Parsberg Werge ◽  
Adrian McCann ◽  
Elisabeth Douglas Galsgaard ◽  
Dorte Holst ◽  
Anne Bugge ◽  
...  
Keyword(s):  
Liver Disease ◽  
Animal Models ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Precise Control ◽  
Transsulfuration Pathway ◽  
Global Population ◽  
Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

scholarly journals Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 145
Author(s):  
Julio Plaza-Díaz ◽  
Patricio Solis-Urra ◽  
Jerónimo Aragón-Vela ◽  
Fernando Rodríguez-Rodríguez ◽  
Jorge Olivares-Arancibia ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Liver Steatosis ◽  
Intestinal Barrier ◽  
Fecal Microbiota ◽  
Current Treatment ◽  
Immune Defense ◽  
Alcoholic Fatty Liver ◽  
The Impact

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health threat and dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma. Several reports have demonstrated that liver steatosis is associated with the elevation of certain clinical and biochemical markers but with low predictive potential. In addition, current imaging methods are inaccurate and inadequate for quantification of liver steatosis and do not distinguish clearly between the microvesicular and the macrovesicular types. On the other hand, an unhealthy status usually presents an altered gut microbiota, associated with the loss of its functions. Indeed, NAFLD pathophysiology has been linked to lower microbial diversity and a weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defense and inflammation via toll-like receptor signaling. Moreover, this activation of inflammation in hepatocytes induces progression from simple steatosis to NASH. In the present review, we aim to: (a) summarize studies on both human and animals addressed to determine the impact of alterations in gut microbiota in NASH; (b) evaluate the potential role of such alterations as biomarkers for prognosis and diagnosis of this disorder; and (c) discuss the involvement of microbiota in the current treatment for NAFLD/NASH (i.e., bariatric surgery, physical exercise and lifestyle, diet, probiotics and prebiotics, and fecal microbiota transplantation).

scholarly journals Target Therapies for NASH/NAFLD: From the Molecular Aspect to the Pharmacological and Surgical Alternatives

2021 ◽  
Vol 11 (6) ◽  
pp. 499
Author(s):  
Michele Finotti ◽  
Maurizio Romano ◽  
Pasquale Auricchio ◽  
Michele Scopelliti ◽  
Marco Brizzolari ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Fatty Liver Disease ◽  
Hepatic Disease ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
Target Therapies ◽  
Chronic Hepatic Disease ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease represents an increasing cause of chronic hepatic disease in recent years. This condition usually arises in patients with multiple comorbidities, the so-called metabolic syndrome. The therapeutic options are multiple, ranging from lifestyle modifications, pharmacological options, to liver transplantation in selected cases. The choice of the most beneficial one and their interactions can be challenging. It is mandatory to stratify the patients according to the severity of their disease to tailor the available treatments. In our contribution, we review the most recent pharmacological target therapies, the role of bariatric surgery, and the impact of liver transplantation on the NAFLD outcome.

scholarly journals Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 102
Author(s):  
Federico Pietrocola ◽  
José Manuel Bravo-San Pedro
Keyword(s):  
Oxidative Stress ◽  
Oxygen Species ◽  
Alcoholic Fatty Liver ◽  
Redox Biology ◽  
Obesity Therapy ◽  
Treatment Of Obesity ◽  
Novel Therapeutic Strategies ◽  
Alcoholic Fatty Liver Disease ◽  
Shed Light

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.

scholarly journals The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 687
Author(s):  
Daniela Gabbia ◽  
Luana Cannella ◽  
Sara De De Martin
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Current Knowledge ◽  
Mechanisms Of Action ◽  
Nadph Oxidases ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

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.

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