Non-Alcoholic Steatohepatitis: Clinical and Translational Research

Neuman, Manuela G.; Voiculescu, M; Nanau, Radu M.; Maor, Yasmin; Melzer, Ehud; Cohen, Lawrence B.; Opris, Mihai; Malnick, Stephen

doi:10.18433/j3f61f

Cited by 5 publications

(5 citation statements)

References 113 publications

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“…Opposite regulation of overlapping fragments might be attributed to changes in the activity of extracellular matrix degrading proteases during fibrosis progression. state to NAFLD and further to NASH on the molecular level is mainly characterized by fibrosis which displays in urinary collagen fragments could be verified in this study [1,2,33]. To select specific fibrosis marker(s), our search strategy for urinary biomarkers was not restricted to a statistical group comparison of peptide distributions in patients with NAFLD and NASH compared to normal individuals, but also extended to patients with LC (both alcohol and non-alcohol aetiology).…”

Section: Discussionsupporting

confidence: 57%

Discovery, validation and sequencing of urinary peptides for diagnosis of liver fibrosis—A multicentre study

et al. 2020

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Background: Liver fibrosis is a consequence of chronic inflammation and is associated with protein changes within the hepatocytes structure. In this study, we aimed to investigate if this is reflected by the urinary proteome and can be explored to diagnose liver fibrosis in patients with chronic liver disease. Methods: In a multicentre combined cross-sectional and prospective diagnostic test validation study, 129 patients with varying degrees of liver fibrosis and 223 controls without liver fibrosis were recruited. Additionally, 41 patients with no liver, but kidney fibrosis were included to evaluate interference with expressions of kidney fibrosis. Urinary low molecular weight proteome was analysed by capillary electrophoresis coupled to mass spectrometry (CE-MS) and a support vector machine marker model was established by integration of peptide markers for liver fibrosis. Findings: CE-MS enabled identification of 50 urinary peptides associated with liver fibrosis. When combined into a classifier, LivFib-50, it separated patients with liver fibrosis (N = 31) from non-liver disease controls (N = 123) in cross-sectional diagnostic phase II evaluation with an area under the curve (AUC) of 0.94 (95% confidence intervals (CI): 0.89À0.97, p<0.0001). When adjusted for age, LivFib-50 demonstrated an AUC of 0.94 (95% CI: 0.89À0.97, p<0.0001) in chronic liver disease patients with (N = 19) or without (N = 17) liver fibrosis progression. In this prospective diagnostic phase III validation set, age-adjusted LivFib-50 showed 84.2% sensitivity (95% CI: 60.4À96.6) and 82.4% specificity (95% CI: 56.6À96.2) for detection of liver fibrosis. The sequence-identified peptides are mainly fragments of collagen chains, uromodulin and Na/K-transporting ATPase subunit g. We also identified ten putative proteolytic cleavage sites, eight were specific for matrix metallopeptidases and two for cathepsins. Interpretation: In liver fibrosis, urinary peptides profiling offers potential diagnostic markers and leads to discovery of proteolytic sites that could be targets for developing anti-fibrotic therapy.

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Section: Discussionsupporting

confidence: 57%

Discovery, validation and sequencing of urinary peptides for diagnosis of liver fibrosis—A multicentre study

et al. 2020

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“…NAFLD is not just a liver disease as it is associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia (Fotbolcu and Zorlu, 2016 ). NAFLD can progress to non-alcoholic steatohepatitis (NASH) where lipid accumulation is accompanied by inflammation (steatohepatitis) that cause irreversible hepatic damage (Neuman et al, 2016 ). Second, alcoholic fatty liver disease (AFLD), the second most common fatty liver condition, is as the name reveals the toxic accumulation of fat as a result of long-term excessive alcohol consumption.…”

Section: Fatty Liver Disease and Steatohepatitismentioning

confidence: 99%

Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy

Asimakopoulou

Weiskirchen

2016

Front. Physiol.

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Lipocalin 2 (LCN2) is a secreted protein that belongs to the Lipocalins, a group of transporters of small lipophilic molecules such as steroids, lipopolysaccharides, iron, and fatty acids in circulation. Two decades after its discovery and after a high variety of published findings, LCN2's altered expression has been assigned to critical roles in several pathological organ conditions, including liver injury and steatosis, renal damage, brain injury, cardiomyopathies, muscle-skeletal disorders, lung infection, and cancer in several organs. The significance of this 25-kDa lipocalin molecule has been impressively increased during the last years. Data from several studies indicate the role of LCN2 in physiological conditions as well as in response to cellular stress and injury. LCN2 in the liver shows a protective role in acute and chronic injury models where its expression is highly elevated. Moreover, LCN2 expression is being considered as a potential strong biomarker for pathological conditions, including rheumatic diseases, cancer in human organs, hepatic steatosis, hepatic damage, and inflammation. In this review, we summarize experimental and clinical findings linking LCN2 to the pathogenesis of liver disease.

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“…According to the recent Centers for Disease Control and Prevention (CDC) reports, 90% of the obese population and 40-70% of the patients with T2DM in the USA are perceived to be suffering from MAFLD. MAFLD is characterized by excess fat accumulation in liver, and it may lead to nonalcoholic steatohepatitis (NASH) in many cases with scarring and inflammation in liver that consequently causes irreversible hepatic damage [3]. Previous studies have described that MAFLD/NASH contributes to disease pathology in several ectopic disorders like type 2 diabetes (T2DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) [4].…”

Section: Introductionmentioning

confidence: 99%

Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis

Mondal

Bose

Saha

et al. 2020

J Neuroinflammation

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Background: Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology. Methods: Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis.Results: Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β. Conclusion:In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.

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Non-Alcoholic Steatohepatitis: Clinical and Translational Research

Abstract: behavior, diet, imaging, non-alcoholic fatty liver, nonalcoholic steatohepatitis, laboratory markers.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Cited by 5 publications

References 113 publications

Discovery, validation and sequencing of urinary peptides for diagnosis of liver fibrosis—A multicentre study

Discovery, validation and sequencing of urinary peptides for diagnosis of liver fibrosis—A multicentre study

Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy

Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis

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