Chronic Non-alcoholic Steatohepatitis Research Articles

The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator.

Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it has emerged as one of the major diseases of the modern world. NAFLD constitutes a simple fatty liver to chronic non-alcoholic steatohepatitis (NASH), which often leads to liver fibrosis or cirrhosis, a serious health condition with limited treatment options. Many a time, NAFLD progresses to fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such as liver X receptor-α (LXR-α) and closely associated farnesoid X receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions and repression and play a major role in controlling the pathophysiology of the human liver. Withaferin A is a multifaceted and potent natural dietary compound with huge beneficial properties and plays a vital role as an anti-inflammatory molecule. Methods: In vivo: Swill albino mice were fed with western diet and sugar water (WDSW) for 12, 16, and 20weeks with suitable controls. Post necropsy, liver enzymes (AST, ALT, and ALP) and lipid profile were measured by commercially available kits using a semi-auto analyzer in serum samples. Liver histology was assessed using H&E and MTS stains to check the inflammation and fibrosis, respectively, using paraffin-embedded sections and mRNA expressions of these markers were measured using qRT-PCR method. TGF-β1 levels in serum samples were quantified by ELISA. In vitro: Steatosis was induced in HepG2 and Huh7 cells using free fatty acids [Sodium Palmitate (SP) and Oleate (OA)]. After induction, the cells were treated with Withaferin A in dose-dependent manner (1, 2.5, and 5 μM, respectively). In vitro steatosis was confirmed by Oil-Red-O staining. Molecular Docking: Studies were conducted using Auto Dock Vina software to check the binding affinity of Withaferin-A to LXR-α and FXR. Results: We explored the dual receptor-activating nature of Withaferin A using docking studies, which potently improves high-fat diet-induced NAFLD in mice and suppresses diet-induced hepatic inflammation and liver fibrosis via LXR/FXR. Our in vitro studies also indicated that Withaferin A inhibits lipid droplet accumulation in sodium palmitate and oleate-treated HepG2 and Huh7 cells, which may occur through LXR-α and FXR-mediated signaling pathways. Withaferin A is a known inhibitor of NF-κB-mediated inflammation. Intriguingly, both LXR-α and FXR activation inhibits inflammation and fibrosis by negatively regulating NF-κB. Additionally, Withaferin A treatment significantly inhibited TGF-β-induced gene expression, which contributes to reduced hepatic fibrosis. Discussion: Thus, the LXR/ FXR dual receptor activator Withaferin A improves both NAFLD-associated liver inflammation and fibrosis in mouse models and under in vitro conditions, which makes Withaferin A a possibly potent pharmacological and therapeutic agent for the treatment of diet-induced NAFLD.

Asociácia nealkoholovej tukovej choroby pečene s kardiálnym štrukturálnym postihnutím

Summary: Non-alcoholic fatty liver disease encompasses a spectrum of pathologic entities ranging from liver steatosis through non-alcoholic steatohepatitis and fibrosis to cirrhosis of the liver. Patients with non-alcoholic fatty liver disease have a higher incidence of coronary artery disease, cardiovascular events due to atherosclerosis, both ischemic and haemorrhagic strokes, thromboembolic events, conduction system disorders, left ventricular dysfunction, and also cardiovascular mortality. Non-alcoholic fatty liver disease is also associated with structural abnormalities of the myocardium and valves. Non-alcoholic steatohepatitis develops in about 8–20% of obese patients with simple hepatic steatosis. The disease tends to progress and may be poorly controlled therapeutically. Non-alcoholic steatohepatitis increases the risk of mortality from cardiovascular disease by 2.1-fold and the risk of mortality from any cause by 2.3-fold. The inflammatory process in the liver may represent a major determinant of systemic complications in people with non-alcoholic fatty liver disease, so its assessment could be useful for cardiovascular risk assessment. Due to the documented association between the severity of hepatic steatosis assessed by ultrasonography and coronary or carotid atherosclerosis, ultrasonographic examination of the liver may be helpful in identifying people at high cardiovascular risk. The present case report confirms the importance of echocardiographic screening for structural and functional cardiac abnormalities in patients with chronic non-alcoholic steatohepatitis in order to initiate early treatment and improve their prognosis. Key words: non-alcoholic fatty liver disease – ultrasonography – echocardiography – screening

A Scoping Review on Lipocalin-2 and Its Role in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma.

Excess calorie intake and a sedentary lifestyle have made non-alcoholic fatty liver disease (NAFLD) one of the fastest growing forms of liver disease of the modern world. It is characterized by abnormal accumulation of fat in the liver and can range from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis as well as development of hepatocellular carcinoma (HCC). Biopsy is the golden standard for the diagnosis and differentiation of all NAFLD stages, but its invasiveness poses a risk for patients, which is why new, non-invasive ways of diagnostics ought to be discovered. Lipocalin-2 (LCN2), which is a part of the lipocalin transport protein family, is a protein formally known for its role in iron transport and in inflammatory response. However, in recent years, its implication in the pathogenesis of NAFLD has become apparent. LCN2 shows significant upregulation in several benign and malignant liver diseases, making it a good candidate for the NAFLD biomarker or even a therapeutic target. What makes LCN2 more interesting to study is the fact that it is overexpressed in HCC development induced by chronic NASH, which is one of the primary causes of cancer-related deaths. However, to this day, neither its role as a biomarker for NAFLD nor the molecular mechanisms of its implication in NAFLD pathogenesis have been completely elucidated. This review aims to gather and closely dissect the current knowledge about, sometimes conflicting, evidence on LCN2 as a biomarker for NAFLD, its involvement in NAFLD, and NAFLD-HCC related pathogenesis, while comparing it to the findings in similar pathologies.

AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis

Chronic nonalcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to liver fibrosis, a condition with limited therapy options. Adiponectin is an adipocytokine that regulates glucose and lipid metabolism via binding to its receptors AdipoR1 and AdipoR2, and AdipoRs signaling is reported to enhance fatty acid oxidation and glucose uptake. Here, we synthesize and report an adiponectin-based agonist JT003, which potently improves insulin resistance in high fat diet induced NASH mice and suppresses hepatic stellate cells (HSCs) activation in CCl4 induced liver fibrosis. Mechanistic studies indicate that JT003 simultaneously stimulates AdipoR1- and AdipoR2- mediated signaling pathways as well as the PI3K-Akt pathway. Moreover, JT003 treatment significantly improves ER-mitochondrial axis function, which contributes to the reduced HSCs activation. Thus, the AdipoR1/AdipoR2 dual agonist improves both NASH and fibrosis in mice models, which provides the pharmacological and biological foundation for developing AdipoRs-based therapeutic agents on liver fibrosis.

Imaging Fibrogenesis in a Diet-Induced Model of Nonalcoholic Steatohepatitis (NASH).

Purpose Liver fibrosis is the hallmark of chronic nonalcoholic steatohepatitis (NASH) and is characterised by the excessive deposition of extracellular matrix proteins. Early detection and accurate staging of liver fibrosis is critically important for patient management. One of the earliest pathological markers in NASH is the activation of hepatic stellate cells (HSCs) which may be exploited as a marker of fibrogenesis. Activated HSCs secreting factors such as integrin αvβ3 propagate fibrosis. The purpose of the current study was to assess the utility of the integrin αvβ3 imaging agent [18F]FtRGD for the early detection of fibrosis in a diet-induced model of NASH longitudinally using PET imaging. Procedures Mice were fed with either standard chow diet (SD), high-fat diet (HFD), or a choline-deficient, L-amino acid-defined high-fat fibrogenic diet (CDAHFD) to mimic the clinical pathology of liver disease and followed longitudinally for 10 weeks to assess the development of liver fibrosis using [18F]FtRGD positron emission tomography (PET) imaging. Standard blood biochemistry, histological measures, and qPCR were used to quantify integrin αvβ3, smooth muscle actin, and collagen types 1 and 6 to assess the extent of NASH pathology and accurately stage liver fibrosis. Results The CDAHFD fibrogenic diet predictably developed hepatic inflammation and steatosis over the 10 weeks studied with little NASH pathology detected in high fat diet-treated animals. Stage 1 fibrosis was detected early by histology at day 21 and progressed to stage 2 by day 35 and stage 3 by day 56 in mice fed with CDAHFD diet only. Noninvasive imaging with [18F]FtRGD correlated well with integrin αvβ3 and was able to distinguish early mild stage 2 fibrosis in CDAHFD animals compared with standard chow diet-fed animals at day 35. When compared with high fat diet-fed animals, [18F]FtRGD was only able to distinguish later moderate stage 2 fibrosis in CDAHFD animals at day 49. Conclusions The diet-induced progression of liver fibrosis was confirmed using histology and correlated well with the mRNA of integrin αvβ3 and extracellular matrix protein expression. [18F]FtRGD showed very good correlation between liver uptake and integrin αvβ3 expression and similar detection sensitivity to the current clinical gold standard modalities for staging of liver fibrosis.

1123 Utility of Non-Invasive Screening Tools for Assessing Liver Fibrosis in Individuals With Medically Complicated Obesity

INTRODUCTION: Individuals with medically-complicated obesity are at risk for cirrhosis as the result of chronic nonalcoholic steatohepatitis (NASH). Several cases of acquired ornithine transcarbamylase (OTC) deficiency have been reported after bariatric surgery, and underlying liver disease is hypothesized as a risk factor. Liver biopsy has been the gold standard for diagnosis and staging of fibrosis, but it is not favored as a screening test due to cost, invasive nature of the test. Commercial blood testing for ALT may be useful for screening for NASH, while the NAFLD Fibrosis Score (NFS) has gained popularity to assess fibrosis. We hypothesize that non-invasive screening can identify both at risk individuals in whom bariatric surgery will potentially halt and reverse fibrosis as well as at risk individuals who should be monitored for signs and symptoms of postoperative OTC deficiency METHODS: This is a retrospective study of 593 consecutive individuals evaluated for bariatric surgery at our urban, community teaching hospital. Each individual is assessed for risk of liver fibrosis with NFS evaluated at their initial visit. ALT levels are also recorded using ACG guidelines for elevation (women > 25 U/L; men > 33 U/L). Intraoperative liver biopsies were suggested in individuals with elevated ALT levels or NFS which was > - 0.70. Steatohepatitis on liver biopsies is staged based on the NAFLD Activity Score (NAS), which in previous studies is reported to have a sensitivity of 43% to 77%. The potential correlation between NFS and NAS is assessed with simple linear regression (Statview, SAS Institute Inc.). RESULTS: Among the 593 subjects, 102 (17.2%) had elevated ALT. Forty-nine individuals underwent liver biopsy (6 for elevated ALT and 43 for NFS > -0.70). Table 1 shows the demographics of these patients. The mean NFS was 0.580 (SD: 1.01) and the mean NAS was 2.9 (SD 1.2). Correlation Coefficient (R: 0.025, P = .86) between NFS calculated at the initial visit and NAS on liver biopsies is not significant. CONCLUSION: Elevated ALT levels may be useful for assessment of risk in individuals with medically-complicated obesity. Our retrospective study has not identified a significant correlation between NFS (from routine parameters) and NAS (from liver biopsies). This finding suggests that NFS is not a sensitive non-invasive screening tool in individuals with medically-complicated obesity. Future studies can be designed to utilize ALT levels and NAS to look at the risk of developing postoperative OTC deficiency.

New approaches to correction of hyperammonemia in patients with non-alcohol steatohepatitis – liquidators of consequences of the accident at Chernobyl APP and personnel of the Federal Fire Service of the EMERCOM of Russia

Relevance.The relevance of this study is determined by the need to correct hyperammonemia in patients with diffuse liver diseases at the pre-cirrhotic stage, since elevated levels of ammonia in the serum have toxic effects on the central nervous system, with the development of hepatic encephalopathy.Intention.To evaluate current medication options for correction of hyperammonemia in chronic non-alcoholic steatohepatitis in the liquidators of the consequences of the accident at the Chernobyl nuclear power plant (NPP) and personnel of the Federal Fire Service (FFS) of the Emercom of Russia.Methodology.34 liquidators of consequences of the accident at the Chernobyl NPP nuclear power plant and 38 employees of the FFS of the Emercom of Russia underwent clinical and laboratory studies, including ammonia levels in blood plasma by enzyme method, evaluation of microbiota disorders, and liver fibrosis grade before and after treatment with L-ornithine-Laspartate (LOLA), as well as a combination of lactulose and a course of rifaximin.Results and Discussion.After correction of hyperammonemia in patients with chronic non-alcoholic steatohepatitis – the liquidators of the consequences of the Chernobyl accident and personnel of the FFS of the Emercom of Russia, there was a decrease in the clinical manifestations of asthenovegetative and dyspeptic syndromes; the incidence of cytolytic and cholestatic syndromes. Besides, intestinal microbiota disorder decreased, as well as fibrotic changes in the liver, and the severity of intrahepatic hemodynamics disorder. In previous studies, the correction of hyperammonemia was mainly carried out with LOLA or lactulose.Conclusion.All liquidators of the consequences of the Chernobyl accident and employees of the FFS of the Emercom of Russia with chronic non-alcoholic steatohepatitis and hyperammonemia should undergo its correction. LOLA is most effective in case of non-cirrhotic portal hypertension and the development of minimal hepatic encephalopathy, and a combination of rifaximin and lactulose is most effective if the intestinal dysbiosis prevails.

The clinical significance of hyperammonemia in the Chernobyl accident liquidators with nonalcoholic steatohepatitis at the precirrotic stage

Relevance. It is known that diffuse liver diseases can be associated with increased ammonia levels in blood serum, that have toxic effects on the central nervous system. Intention. To establish the clinical importance of hyperammonemia in chronic non-alcoholic steatohepatitis in the liquidators of Chernobyl nuclear power (CNPP) plant accident aftermath. Methods. In 65 Chernobyl accident liquidators, liver fibrosis, plasma ammonia levels were also assessed via enzyme method in addition to general clinical examination, including microbiota disorders. Results and Discussion. Hyperammonemia was detected in 46 % of liquidators with chronic nonalcoholic steatohepatitis, with greater severity of clinical manifestations of asthenic-vegetative and dyspeptic syndromes, liver fibrosis and disorders of intestinal microbiota and intrahepatic hemodynamics, including noncyrrotic portal hypertension. In previous studies, the role of hyperammonemia was mainly studied at the stage of the formed cirrhosis of the liver accompanied by the hepatic encephalopathy. Conclusion. It is necessary to determine the level of ammonia in the blood plasma in all liquidators of CNPP accident aftermath suffering from chronic non-alcoholic steatohepatitis.

Phlebotomy reduces transaminase levels in patients with chronic non-alcoholic steatohepatitis

Phlebotomy reduces transaminase levels in patients with chronic non-alcoholic steatohepatitis