Quantitative Assessment of Liver Steatosis and Affected Pathways with Molecular Imaging and Proteomic Profiling.
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ABSTRACT:
SUBMITTER: Urasaki Y
PROVIDER: S-EPMC5826939 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background Advanced confounder-corrected chemical shift-encoded MRI-derived proton density fat fraction (PDFF) is a leading parameter for fat fraction quantification in nonalcoholic fatty liver disease (NAFLD). Because of the limited availability of this MRI technique, there is a need to develop and validate alternative parameters to assess liver fat. Purpose To assess relationship of quantitative US parameters to MRI PDFF and to develop multivariable quantitative US models to detect hepatic steatosis and quantify hepatic fat. Materials and Methods Adults with known NAFLD or who were suspected of having NAFLD were prospectively recruited between August 2015 and February 2019. Participants underwent quantitative US and chemical shift-encoded MRI liver examinations. Liver biopsies were performed if clinically indicated. The correlation between seven quantitative US parameters and MRI PDFF was evaluated. By using leave-one-out cross validation, two quantitative US multivariable models were evaluated: a classifier to differentiate participants with NAFLD versus participants without NAFLD and a fat fraction estimator. Classifier performance was summarized by area under the receiver operating characteristic curve and area under the precision-recall curve. Fat fraction estimator performance was evaluated by correlation, linearity, and bias. Results Included were 102 participants (mean age, 52 years ± 13 [standard deviation]; 53 women), 78 with NAFLD (MRI PDFF ≥ 5%). A two-variable classifier yielded a cross-validated area under the receiver operating characteristic curve of 0.89 (95% confidence interval: 0.82, 0.96) and an area under the precision-recall curve of 0.96 (95% confidence interval: 0.93, 0.99). The cross-validated fat fraction predicted by a two-variable fat fraction estimator was correlated with MRI PDFF (Spearman ρ = 0.82 [P < .001]; Pearson r = 0.76 [P < .001]). The mean bias was 0.02% (P = .97), and 95% limits of agreement were ±12.0%. The predicted fat fraction was linear with MRI PDFF (R 2 = 0.63; slope, 0.69; intercept, 4.3%) for MRI PDFF of 34% or less. Conclusion A multivariable quantitative US approach yielded excellent correlation with MRI proton density fat fraction for hepatic steatosis assessment in nonalcoholic fatty liver disease. © RSNA, 2020 Online supplemental material is available for this article.
| S-EPMC7104700 | biostudies-literature
Project description:BackgroundControlled attenuation parameter (CAP) without the guidance of the grey scale sonogram was a classic method in the quantitative evaluation of liver steatosis, it is recommended by international guidelines. Our study aimed to compare the diagnostic efficiency of a new real-time visual liver steatosis analysis (LiSA) versus CAP in chronic hepatitis B patients with liver steatosis.MethodsPatients were enrolled who underwent liver biopsy and received both LiSA (Hepatus, Mindray, probe LFP5-1U/s, China) and CAP (FibroScan502, Echosens, probe M, France) measurement simultaneously in our hospital from November 2018 to December 2019. The obtained values were both expressed as dB/m. Based on the liver fat content validated by liver biopsy, these patients were divided into the S0 group (fat content <5%) and S1 group (fat content ≥5%). The efficiency of the LiSA and CAP value in the diagnosis of liver steatosis was evaluated. Independent factors influencing the LiSA value were predicted by correlation analysis and multiple linear regression analysis.ResultsA total of 151 patients were included in the analysis according to the exclusion criteria from 304 enrolled liver biopsy chronic hepatitis B (CHB) patients. Both LiSA and CAP successfully differentiated the S0 group from the S1 group. Receiver operating characteristic (ROC) curves showed that both LiSA and CAP had good diagnostic performance [area under the ROC curve area under the curve (AUC) >0.7] in evaluating liver steatosis, while there was no significant difference between the 2 methods (AUC 0.825 vs. 0.798, P=0.067). Using the optimal cutoff point, the specificity and sensitivity of LiSA in diagnosing liver steatosis were 89.18% and 79.16%, respectively. The specificity and sensitivity of CAP in diagnosing liver steatosis were 87.20% and 76.31%, respectively.ConclusionsBoth LiSA and CAP are efficient for evaluating liver steatosis noninvasively.
| S-EPMC9011258 | biostudies-literature
Project description:Pancreatic β-cell dysfunction and reduced insulin secretion play a key role in the pathogenesis of diabetes. Fetal and neonatal islets are functionally immature and have blunted glucose responsiveness and decreased insulin secretion in response to stimuli and are far more proliferative. However, the mechanisms underlying functional immaturity are not well understood. Pancreatic islets are composed of a mixture of different cell types, and the microenvironment of islets and interactions between these cell types are critical for β-cell development and maturation. RNA sequencing and quantitative proteomic data from intact islets isolated from fetal (embryonic day 19) and 2-week-old Sprague-Dawley rats were integrated to compare their gene and protein expression profiles. Ingenuity Pathway Analysis (IPA) was also applied to elucidate pathways and upstream regulators modulating functional maturation of islets. By integrating transcriptome and proteomic data, 917 differentially expressed genes/proteins were identified with a false discovery rate of less than 0.05. A total of 411 and 506 of them were upregulated and downregulated in the 2-week-old islets, respectively. IPA revealed novel critical pathways associated with functional maturation of islets, such as AMPK (adenosine monophosphate-activated protein kinase) and aryl hydrocarbon receptor signaling, as well as the importance of lipid homeostasis/signaling and neuronal function. Furthermore, we also identified many proteins enriched either in fetal or 2-week-old islets related to extracellular matrix and cell communication, suggesting that these pathways play critical roles in islet maturation. Our present study identified novel pathways for mature islet function in addition to confirming previously reported mechanisms, and provided new mechanistic insights for future research on diabetes prevention and treatment.
| S-EPMC7668240 | biostudies-literature
Project description:Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging with MPO-Gd. Saline-injected and control diet-fed leptin receptor-deficient mice were used as respective controls. MPO protein and activity measurements and histologic analyses were performed. Eleven human liver biopsy samples underwent MPO-Gd-enhanced MR imaging ex vivo and subsequent histologic evaluation. Results were compared with Student t test or Mann-Whitney U test. Results With endotoxin, a significantly increased contrast-to-noise ratio (CNR) was found compared with sham (mean CNR, 1.81 [95% confidence interval {CI}: 1.53, 2.10] vs 1.02 [95% CI: 0.89, 1.14]; P = .03) at MPO-Gd MR imaging. In the diet-induced NASH model, an increased CNR was also found compared with sham mice (mean CNR, 1.33 [95% CI: 1.27, 1.40] vs 0.98 [95% CI: 0.83, 1.12]; P = .008). Conversely, CNR remained at baseline in NASH mice imaged with gadopentetate dimeglumine and in MPO knockout NASH mice with MPO-Gd, which proves specificity of MPO-Gd. Ex vivo molecular MR imaging of liver biopsy samples from NASH and control patients confirmed results from animal studies (mean CNR for NASH vs control patients, 2.61 [95% CI: 1.48, 3.74] vs 1.29 [95% CI: 1.06, 1.52]; P = .004). Conclusion MPO-Gd showed elevated MPO activity in NAFLD mouse models and human liver biopsy samples. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on April 6, 2017.
| S-EPMC5548451 | biostudies-literature
Project description:ObjectiveTo develop a quantitative ultrasound (QUS)- and elastography-based model to improve classification of steatosis grade, inflammation grade, and fibrosis stage in patients with chronic liver disease in comparison with shear wave elastography alone, using histopathology as the reference standard.MethodsThis ancillary study to a prospective institutional review-board approved study included 82 patients with non-alcoholic fatty liver disease, chronic hepatitis B or C virus, or autoimmune hepatitis. Elastography measurements, homodyned K-distribution parametric maps, and total attenuation coefficient slope were recorded. Random forests classification and bootstrapping were used to identify combinations of parameters that provided the highest diagnostic accuracy. Receiver operating characteristic (ROC) curves were computed.ResultsFor classification of steatosis grade S0 vs. S1-3, S0-1 vs. S2-3, S0-2 vs. S3, area under the receiver operating characteristic curve (AUC) were respectively 0.60, 0.63, and 0.62 with elasticity alone, and 0.90, 0.81, and 0.78 with the best tested model combining QUS and elastography features. For classification of inflammation grade A0 vs. A1-3, A0-1 vs. A2-3, A0-2 vs. A3, AUCs were respectively 0.56, 0.62, and 0.64 with elasticity alone, and 0.75, 0.68, and 0.69 with the best model. For classification of liver fibrosis stage F0 vs. F1-4, F0-1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4, AUCs were respectively 0.66, 0.77, 0.72, and 0.74 with elasticity alone, and 0.72, 0.77, 0.77, and 0.75 with the best model.ConclusionRandom forest models incorporating QUS and shear wave elastography increased the classification accuracy of liver steatosis, inflammation, and fibrosis when compared to shear wave elastography alone.
| S-EPMC8794185 | biostudies-literature
Project description:BackgroundNutrient excess underpins the development of nonalcoholic fatty liver disease (NAFLD). The ensuing metabolic derangement is characterised by increased cellular respiration, oxidative stress and mitochondrial impairment. We have previously recapitulated these events in an in vitro cellular steatosis model. Here, we examined the distinct patterns of protein expression involved using a proteomics approach.MethodsHuman hepatoblastoma C3A cells were treated with a combination of energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N). Proteins extracts were trypsinized and analyzed on a capillary HPLC OrbitrapXL mass spectrometer. Proteins were quantified using a label-free intensity based approach. Functional enrichment analysis was performed using ToppCluster via Gene Ontology (GO) database.ResultsOf the 1327 proteins identified, 104 were differentially expressed between LPON and untreated cells (defined as: ≥2 peptides; fold change ≥1.5; p-value <0.05). Seventy of these were upregulated with LPON. Functional enrichment analysis revealed enhanced protein biosynthesis accompanied by downregulation of histones H2A type 1-A, H1.2, H1.5 and H1.0I in LPON cells. Lipid binding annotations were also enriched as well as proteins involved in cholesterol synthesis, uptake and efflux. Increased expression of aldo-keto reductase family 1, member C1 and C3 suggests enhanced sterol metabolism and increased ROS-mediated lipid peroxidation.ConclusionsThe surge of energy substrates diverts free fatty acid metabolism towards pathways that can mitigate lipotoxicity. The histones depletion may represent an adaptation to increased protein synthesis. However, this can also expose DNA to oxidative stress thus should be explored further in the context of NAFLD progression.
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Project description:Lung cancer remains the leading cancer killer around the world. It's crucial to identify newer mechanism-based targets to effectively manage lung cancer. Annexin A5 (ANXA5) is a protein kinase C inhibitory protein and calcium dependent phospholipid-binding protein, which may act as an endogenous regulator of various pathophysiological processes. However, its molecular mechanism in lung cancer remains poorly understood. This study was designed to determine the mechanism of ANXA5 in lung cancer with a hope to obtain useful information to provide a new therapeutic target. We used a stable isotope dimethyl labeling based quantitative proteomic method to identify differentially expressed proteins in NSCLC cell lines after ANXA5 transfection. Out of 314 proteins, we identified 26 and 44 proteins that were down- and up-regulated upon ANXA5 modulation, respectively. The IPA analysis revealed that glycolysis and gluconeogenesis were the predominant pathways modulated by ANXA5. Multiple central nodes, namely HSPA5, FN1, PDIA6, ENO1, ALDOA, JUP and KRT6A appeared to occupy regulatory nodes in the protein-protein networks upon ANXA5 modulation. Taken together, ANXA5 appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of ANXA5 as a potential target in lung cancer. This study might provide a new insight into the mechanism of ANXA5 in lung cancer.
| S-EPMC5042544 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver disease that progressively develops in four stages (steatosis, non-alcoholic steatohepatitis-NASH, fibrosis, cirrhosis). In order to accurately evaluate the amount of fat content inside the hepatocytes, non-invasive imaging studies such as magnetic resonance spectroscopy (MRS) of the liver can be used as an alternative method to the traditional invasive liver biopsy. The main objective of our study was to quantitatively assess hepatic steatosis before and after treatment using liver MRS. The study group included 35 patients diagnosed with NAFLD who freely expressed their agreement to take part in this study. The treatment lasted 6 months and consisted of administering a local commercially available liver protection supplement combined with dietary and lifestyle adjustments. The initial quantitative assessment of the liver fat content using MRS revealed a hepatic lipid accumulation ranging from 15.70% to 68.03%, with a mean value of 41.26%. The subsequent liver MRS performed after 6 months of proper treatment indicated a fat content inside the liver parenchyma ranging from 15.47% to 58.98%, with a mean value of 36.07%. The therapeutic measures that were applied to the patients managed to reduce the amount of fat content inside the liver parenchyma in 24 patients (68.57%), while in 11 patients (31.43%) the results revealed an increase in hepatic lipid content. In conclusion, the current study reached its initial objective and offered a modern approach regarding the pre and post-treatment evaluation of hepatic steatosis using MRS.
| S-EPMC6993765 | biostudies-literature
Project description:Long-term consumption of sodium arsenite contaminated water can cause endemic arsenic disease. The proteome profile changes of liver fibrosis after exposure to arsenite containing water remain unclear. In this study, Sprague-Dawley (SD) male rats were treated with sodium arsenite (iAs3+), using a daily dose of 1.36?mg/kg body weight (medium dose group, M), 2.73?mg/kg body weight (high dose group, H) or deionized water (control group, C). Isobaric tags for relative and absolute quantitation (iTRAQ) were used to identify the different abundant proteins (DAPs) after arsenic-induced liver fibrosis. A total of 2987 high-quality proteins were detected (95% confident peptides???2), 608 of which were differentially expressed (fold change?>?2 and p?<?0.05) in M group and 475 in H group. Moreover, 431 DAPs were found in both M and H groups and used in subsequent bioinformatic analyses. Gene ontology (GO) analysis revealed 4,709 GO terms could be mapped, among which purine binding, actin filament binding and protein kinase binding were the most enriched terms for molecular function category. In addition, protein-protein interaction analysis showed six clusters of interaction networks. Our data provided new insights into the proteome changes after arsenic-induced liver fibrosis in model rats.
| S-EPMC5818499 | biostudies-literature
Project description:PANcreatic-DERived factor (PANDER) is a member of a superfamily of FAM3 proteins modulating glycemic levels by metabolic regulation of the liver and pancreas. The precise PANDER-induced hepatic signaling mechanism is still being elucidated and has been very complex due to the pleiotropic nature of this novel hormone. Our PANDER transgenic (PANTG) mouse displays a selective hepatic insulin resistant (SHIR) phenotype whereby insulin signaling is blunted yet lipogenesis is increased, a phenomena observed in type 2 diabetes. To examine the complex PANDER-induced mechanism of SHIR, we utilized quantitative mass spectrometry-based proteomic analysis using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) to reveal the global hepatic proteome differences within the PANTG under the metabolic states of fasting, fed and insulin-stimulated conditions. Proteomic analysis identified lipid metabolism as one of the top cellular functions differentially altered in all metabolic states. Differentially expressed proteins within the PANTG having a lipid metabolic role included ACC, ACLY, CD36, CYP7A1, FASN and SCD1. Central to the differentially expressed proteins involved in lipid metabolism was the predicted activation of the liver X receptor (LXR) pathway. Western analysis validated the increased hepatic expression of LXR? along with LXR-directed targets such as FASN and CYP7A1 within the PANTG liver. Furthermore, recombinant PANDER was capable of inducing LXR promoter activity in-vitro as determined by luciferase reporter assays. Taken together, PANDER strongly impacts hepatic lipid metabolism across metabolic states and may induce a SHIR phenotype via the LXR pathway.
| S-EPMC5789791 | biostudies-literature