NASH Group Research Articles

Assessment of Pro Collagen III as Non Invasive Biomarker for Diagnosis of Non Alcoholic Steatohepatitis

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. NAFLD is considered to represent the hepatic manifestation of metabolic syndrome. NAFLD was traditionally considered as a relatively benign liver disease. However, some patients with NAFLD progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. Therefore, the precise diagnosis and staging of NAFLD patients is clinically important. Liver biopsy is the current gold standard in diagnosis and prognosis. Because of poor patient acceptance of this invasive standard technique and Significant sampling variability of routine liver biopsy in patients with NAFLD, there is an urgent need for reliable, accurate, and non- or minimally invasive biomarker. Aim of the Work Assess the performance of Pro Collagen III As a NASH-Fibrosis biomarker within the best diagnostic context of use in comparison with FIB-4 Patients and Methods this study is a Case control study. Gastroenterology and Hepatology outpatient clinic at Damas centre for liver and GIT. 6 months from August 2022 to January 2023. This study will be performed on 56 Egyptian patients who are ≥18years of age and are overweight with Body Mass Index ≥ 25 and diagnosed with NAFLD by US. Results As regard age; there is no significant difference between NAFL and NASH groups. As regard sex; there is no significant difference between NAFL and NASH groups. The mean BMI was significant higher in NASH group than NAFLD group. Patients with NASH have relatively low platelet count in comparison with NAFLD patients. Patients with NASH has Higher AST & ALT levels than NAFLD patients. FIB-4 was higher in NASH group than NAFLD group. Pro Collagen III level was higher in patients with NASH than Patients with NAFLD. Pro Collagen III was a significant discriminator of NAFLD & NASH. Pro Collagen III correlates with the grades of histological steatohepatitis, and stage of fibrosis. Pro Collagen III can diagnose steatohepatitis at cut-off 9.57 with sensitivity & specificity was 92.9 & 92.9 respectively. Conclusion Pro Collagen III is a sensitive biomarker to discriminate between NAFLD & NASH. Pro Collagen III level correlate positively with BMI, AST & ALT. Pro Collagen III level correlate with grades of histological steatohepatitis, and grades of fibrosis.

A Stone–von Neumann equivalence of categories for smooth representations of the Heisenberg group

The classical Stone–von Neumann theorem relates the irreducible unitary representations of the Heisenberg group Hn to non-trivial unitary characters of its center Z, and plays a crucial role in the construction of the oscillator representation for the metaplectic group. In this paper we extend these ideas to non-unitary and non-irreducible representations, thereby obtaining an equivalence of categories between certain representations of Z and those of Hn. Our main result is a smooth equivalence, which involves the fundamental ideas of du Cloux on differentiable representations and smooth imprimitivity systems for Nash groups. We show how to extend the oscillator representation to the smooth setting and give an application to degenerate Whittaker models for representations of reductive groups. We also include an algebraic equivalence, which can be regarded as a generalization of Kashiwara’s lemma from the theory of D-modules.

The function role of HIGD1A in nonalcoholic steatohepatitis from chronic hepatitis B

Background Accompanied by the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the coexistence of chronic hepatitis B (CHB) and NAFLD has increased. In the context of CHB, there is limited understanding of the factors that influence the development of NASH. Methods We enrolled CHB combined NAFLD patients who had liver biopsy and divided them to NASH vs. non-NASH groups. A whole transcriptome chip was used to examine the expression profiles of long noncoding RNAs (lncRNAs) and mRNA in biopsied liver tissues. The function analysis of HIGD1A were performed. We knocked down or overexpressed HIGD1A in HepG2.2.15 cells by transient transfection of siRNA-HIGD1A or pcDNA-HIGD1A. In vivo investigations were conducted using hepatitis B virus (HBV) transgenic mice. Results In 65 patients with CHB and NAFLD, 28 were patients with NASH, and 37 were those without NASH. After screening 582 differentially expressed mRNAs, GO analysis revealed differentially expressed mRNAs acting on nicotinamide adenine dinucleotide phosphate (NADPH), which influenced redox enzyme activity. KEGG analysis also shown that they were involved in the NAFLD signaling pathway. The function analysis revealed that HIGD1A was associated with the mitochondrion. Then, both in vivo and in vitro CHB model, HIGD1A was significantly higher in the NASH group than in the non-NASH group. HIGD1A knockdown impaired mitochondrial transmembrane potential and induced cell apoptosis in HepG2.2.15 cells added oleic acid and palmitate. On the contrary, hepatic HIGD1A overexpression ameliorated free fatty acids-induced apoptosis and oxidative stress. Furthermore, HIGD1A reduced reactive oxygen species (ROS) level by increasing glutathione (GSH) expression, but Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK)/Acetyl-CoA carboxylase (ACC) pathway was not involved. Conclusion Both in vivo and in vitro CHB model, an upward trend of HIGD1A was observed in the NASH-related inflammatory response. HIGDIA played a protective role in cells against oxidative stress. Our data suggested that HIGD1A may be a positive regulator of NASH within the CHB context.

Study on the correlation between type 2 diabetes mellitus combined with non-alcoholic steatohepatitis and aerobic exercise performance

Objective: To study the correlation between patients with type 2 diabetes mellitus combined with nonalcoholic steatohepatitis in order to provide theoretical support for the treatment of NAFLD through aerobic exercise performance. Methods: 253 cases with T2DM combined with NAFLD were selected. 93 cases consented to undergo a liver biopsy. Among them, 74 cases with liver biopsy successfully passed the symptom-limited cardiopulmonary exercise test (CPET) and respiratory quotient (RQ)≥1.05. Patients were divided into two groups according to the NAFLD activity score (NAS) of the pathological biopsy: the non-NASH group (NAS < 4) and the NASH group (NAS≥4). The differences in general clinical and biochemical indicators and exercise parameters were compared between the two groups. The relevant factors that affect aerobic exercise performance in NAFLD patients were explored by correlation and regression analysis. Results: The peak oxygen uptake [VO2 @ peak, (17.82 ± 5.61) ml·kg(-1)·min(-1) and (23.14 ± 5.86) ml·kg(-1)·min(-1)] and anaerobic threshold [VO2 @ AT, (11.47 ± 3.12) ml·kg(-1)·min(-1) and (13.81 ± 3.53) ml·kg(-1)·min(-1)] were lower in the NASH group than those in the non-NASH group in T2DM patients, with P < 0.01, indicating a significant decrease in aerobic exercise performance in NASH patients compared to non-NASH patients. Correlation analysis showed that patients with T2DM combined with NAFLD VO2@peak was positively correlated with RQ, carbohydrate oxidation rate (%CHO), daily carbohydrate energy supply (CHO Kcal/d), high-density lipoprotein cholesterol (HDL-C), and maximal voluntary ventilation (MVV) (r 0.360, 0.334, 0.341, 0.255, 0.294, P < 0.05 or P < 0.01, respectively) and negatively correlated with NAS score, fat attenuation, liver stiffness, fat oxidation rate (%FAT), daily fat energy supply (FAT Kcal/d), aspartate aminotransferase (AST), alanine aminotransferase (ALT), body mass, and body mass index (BMI) (r -0.558, -0.411, -0.437, -0.340, -0.270, -0.288, -0.331, -0.295, -0.469, P < 0.05 or P < 0.01, respectively). VO2@AT were positively correlated with RQ, %CHO, total cholesterol (TC), and HDL-C (r 0.351, 0.247, 0.303, 0.380, P < 0.05 or P < 0.01, respectively), while it was negatively correlated with NAS score, fat attenuation, liver stiffness, %FAT, FAT (Kcal/d), ferritin (Fer), ALT, AST, body weight, and BMI (r -0.330, -0.384, -0.428, -0.270, -0.318, 0.320, -0.404, -0.416, -0.389, -0.520, P < 0.05 or P < 0.01, respectively). Stepwise multiple regression analyses revealed that BMI, RQ, and NAS scores were independent correlated factors of aerobic exercise performance. Conclusion: Hepatic inflammation and fibrosis affect the aerobic exercise performance of patients with T2DM combined with NAFLD.

Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model.

NASH is an increasingly common cause of chronic liver disease and can progress to cirrhosis and HCC. Although exercise suppresses inflammation during acute hepatitis, its impact on the progression of chronic liver disease remains unclear. Here, we investigated the effects of exercise on disease progression and intrahepatic immune cell composition in a mouse model of NASH. Mice were assigned to 4 groups: 2 control groups (normal diet) and 2 NASH groups (western diet and low-dose carbon tetrachloride injection). One of each group remained sedentary and one was exercised on a treadmill for 12 weeks (60min/d, 5 times/wk). All mice were then analyzed for liver histomorphology, steatosis, inflammation, and fibrosis; liver, adipose tissue, and skeletal muscle expression of genes related to metabolism and inflammation; and intrahepatic immune cell composition. Compared with the normal diet mice, NASH mice exhibited enhanced liver steatosis, inflammation, and fibrosis; upregulated expression of liver lipogenesis-related and inflammation-related genes; and increased frequencies of intrahepatic F4/80 int CD11b hi bone marrow-derived macrophages and programmed death receptor-1 (PD-1) + CD8 + T cells. Expression of inflammatory cytokines and the frequencies of bone marrow-derived macrophages and PD-1 + CD8 + T cells correlated positively with liver steatosis, inflammation, and fibrosis. Exercise was shown to reduce NASH-induced hepatic steatosis, liver inflammation, and fibrosis; induce alterations in metabolism-related genes and inflammatory cytokines in the liver; and suppress accumulation of liver bone marrow-derived macrophages and PD-1 + CD8 + T cells. In addition, we showed that exercise induced increased expression of IL-15 in muscle and its deficiency exacerbated the pathology of NASH. Exercise alters the intrahepatic immune cell profile and protects against disease progression in a mouse model of NASH.

Development, Validation, and Application of a Scoring Model for Non-alcoholic Steatohepatitis.

The aim of this study was to explore risk factors of NASH and then develop a non-invasive scoring model in Chinese patients with obesity. A scoring system was then applied to assess the effect of sleeve gastrectomy on NASH. A total of 243 patients with obesity were included and divided into NASH group and non-NASH group according to the pathological results of liver biopsy. Logistic regression was used to determine risk factors of NASH. A scoring model was derived by risk factors of NASH. Then, postoperative follow-up was performed in 70 patients. Among the 243 patients, 118 (48.56%) patients showed NASH. Multivariate logistic regression identified aspartate aminotransferase (AST) (>21.50 IU/L), high-density lipoprotein cholesterol (HDL-C) (<1.155mmol/L), and homeostasis model assessment (HOMA-IR) (>9.368) as independent risk factors of NASH. The model included above risk factors showed a negative predictive value (NPV) of 70.38% in the low-risk category and a positive predictive value (PPV) of 85.71% in the high-risk category, with the area under the receiver operator curve (AUROC) of 0.737. Bariatric surgery resulted in a sharp decline in AST and HOMA-IR and a significant increase of HDL-C. The points of scoring model were improved at 6 months after surgery. A non-invasive scoring model was derived by the risk factors of NASH included AST, HDL-C, and HOMA-IR and applied to the postoperative follow-up. After sleeve gastrectomy, the above risk factors and points of scoring model were significantly improved.

Study Association of Serum Immunoglobulins and Non-Alcoholic Fatty Liver Disease in Egyptian Patients

Abstract Background Non-alcoholic fatty liver disease represents a spectrum of liver diseases which occurs in the absence of alcohol consumption, it has become a clinical burden around the world because of its independent relationship with increased risks of cardiovascular disease, hyperglycemia and tumor malignancy, as an example it's the most common chronic liver disease in North America, with reported prevalence rates of 10%–50% in the general population. However, only 10%–30% of NAFLD patients progress to advanced fibrosis, cirrhosis, and/or hepatocellular carcinoma. Aim of the Work The aim of this study was to further investigate the association between NAFLD and the serum immunoglobulins. Patients and Methods Atotal of one hundred Egyptian people were enrolled in the study and divided into two groups: Group 1: 50 patients with non-alcoholic fatty liver disease diagnosed by clinical, laboratory and radiological investigations. Group 2: 50 patients with non-alcoholic steatohepatitis diagnosed by clinical, radiological features of NAFLD and elevated liver enzymes. Results Results of the present study revealed that the mean age of NAFLD was 44.4±9.3 and in NASH 50.6±8.5. In our study it was proven that Nafld prevalence increases with age. Concerning gender in our study there was predominance of female gender in NASH group by about 70% but in NAFLD they represent only 48%. In our study, it was proven that BMI and waist circumference were signifcnatly higher in NASH group. DM were signifciantly more frequent in NASH group. In the present study, there was no significant difference between the studied groups regarding hemoglobin, TLC and platelets. Conclusion Our results revealed that IgA was significantly higher among NASH group, IgM and IgG were significantly higher among NAFLD group. Results of this study showed statistically significant relation between ALT, AST, GGT and INR and degree of steatosis, they were higher among NASH group and also the albumin was significantly lower among NASH group on the other hand bilirubin was non-significantly higher in NASH.

Usefullness of a Combined Evaluation of the Serum Adiponectin Level and Insulin Growth Factor 1 to Predict the Early Stage of Nonalcoholic Steatohepatitis

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western industrialised countries and affects around 25% of the European population. The prevalence of NAFLD is increasing in parallel with the global increase in obesity and type 2 diabetes mellitus (T2DM). Aim of the Work To investigate the role of adiponectin and IGF1 in the diagnosis of NASH. Patients and Methods The present study included 60 patients who attending the outpatient clinic of Ain Shams University hospital, they age ranges from thirty to sixty years. Results It was found that highly significant decrease in Adiponectin and IGF-1 levels, in NASH group; compared to NAFLD control group (p &amp;lt; 0.01 respectively) a This data is similar to many studies done before in NAFLD and NASH patients. Our study also shows that; AST, ALT, total and direct bilirubin, had a highly significant negative correlation with IGF-1 and Adiponectin level (p &amp;lt; 0.01 respectively). This go with many studies who found a significant inverse correlation between IGF-I levels and liver enzymes, indicating that lower IGF-I levels in NAFLD are related to parenchymal dysfunction. With proven evidence that low circulating IGF-I levels correlate with the degree of liver dysfunction. Conclusion Serum adiponectin and insulin growth factor 1 are lower in patients with NASH compared to NAFLD patients which reflect the protective effect of both of adiponectin and IGF1 against the development of NASH.

Role of Circulating Vascular Cell Adhesion Protein – 1 as a Biomarker in Non-alcoholic Fatty Liver Disease

Background As a result of the obesity pandemic, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. NAFLD is the hepatic manifestation of obesity and a precursor of and independent risk factor for type 2 diabetes Aim of the Work To assess the level of vascular cell adhesion molecule 1 (VCAM-1) as noninvasive diagnostic tools for diagnosis of NAFLD degree of fibrosis. Patients and Methods A Case-Control clinical study in the Internal medicine and hepatology outpatient clinic at Ain Shams University Hospital for 6-month on 60 persons that were included in this study divided into 2 groups: Group A: 30 patient with NAFLD as a study group. Group B: 30 healthy subjects as a control group. Results In the present study, the mean VCAM-1 was 2.392 ± 0.3 in NAFLD group, 9.893 ± 2.3 in NASH group and 1.983 ± 0.3 in control group with high statistical significant increase in NASH followed by NAFLD than in control group. Regarding to ROC curve, VCAM-1 had excellent Diagnostic performance with an AUC of 0.994. A best cut-off criterion of VCAM-1 &amp;gt; 7.7 ng/mL could discriminate between patients with NASH from control group with a sensitivity of 95% and specificity of 100% In our study, there was no significant correlation in between VCAM-1 and age, AST, ALT In the present study, the significant predictors of bad outcome in patients with NAFLD and NASH were higher VCAM-1 level, GGT and higher AST levels Conclusion The significant predictors of bad outcome in patients with NAFLD and NASH were higher VCAM-1 level, GGT and higher AST levels.

A nonabelian Brunn–Minkowski inequality

Henstock and Macbeath asked in 1953 whether the Brunn–Minkowski inequality can be generalized to nonabelian locally compact groups; questions along the same line were also asked by Hrushovski, McCrudden, and Tao. We obtain here such an inequality and prove that it is sharp for helix-free locally compact groups, which includes real linear algebraic groups, Nash groups, semisimple Lie groups with finite center, solvable Lie groups, etc. The proof follows an induction on dimension strategy; new ingredients include an understanding of the role played by maximal compact subgroups of Lie groups, a necessary modified form of the inequality which is also applicable to nonunimodular locally compact groups, and a proportionated averaging trick.

Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium

NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients' PBMCs there were no differences in the expression of genes regulating β-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.

Dietary methionine restriction attenuates cognitive dysfunction associated with sleep deprivation by promoting production of hydrogen sulfide, upregulating expression of BDNF and suppressing neuro-inflammation in rats

IntroductionIn this study, we aimed to study the potential role of H2S and the application of dietary methionine restriction (DMR) in the treatment of cognitive dysfunction in sleep deprived rat models.Material and methodsThe rat groups were established as a Control group, a sleep deprivation (SD) group, a SD + NaSH group and a SD + DMR group. Behavioral data was studied via Morris water maze test. TUNEL assay, real-time PCR, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were performed to study the differences of cognitive impairment related genes and proteins in different rat groups.ResultsPath length and escape latency were higher in the sleep deprived rats compared with the control rats, which were subsequently recovered by the treatment of NaSH or DMR. Also, DMR most significantly recovered the cognitive impairment and neuron status of sleep deprived rats compared with the administration of NaSH. The elevated level of hippocampal Iba1 and H2S production was recovered by NaSH and DMR, and the expressions of hippocampal phenotypic-related genes including NOS, CD68, CD32 and CD206 mRNA also showed similar trend as hippocampal Iba1. Meanwhile, the increased relative expression of IL-6 and IL-4 were recovered by DMR in sleep deprived rats, while the reduced level of hippocampal brain-derived neurotrophic factor (BDNF) and cystathionine γ-lyase (CSE) were elevated by the treatment of NaSH and MDR, with MDR exhibiting the most significant effect.ConclusionsThe application of DMR could attenuate cognitive dysfunction in sleep deprivation rats by upregulating the production of H2S and BDNF expression and alleviating neuro-inflammation responses.

The prophylactic treatment of Egyptian, Trigonella foenum - graecum L., Extract in comparison to pure diosgenin on experimentally induced non-alcoholic steatohepatitis: New targets via AMPK, RAR, and FXR pathways

BackgroundNon-alcoholic steatohepatitis (NASH) is an inflammatory liver condition that damages the liver by accumulating fat. AimOur study sought to explore the mechanisms involved through which fengreek, Trigonella foenum - graecum L., extract (FE) or diosgenin (DSG) exerted their hepatoprotective activity in NASH-induced rat model. MethodsFE was prepared via a Soxhlet extraction, followed by acid hydrolysis. Sixty male albino rats were randomly distributed into six groups: normal control (NC) group, NASH-control group, FE group, low DSG dose (LD-1) group, medium DSG dose (MD-5) group, and high DSG dose (HD-10) group. The influence of both FE and pure DSG on serum liver indices, lipid profile, glucose, insulin, and Homeostasis model assessment (HOMA) of insulin resistance (IR) were determined. Liver histopathology, liver gene expression of adenosine monophosphate (AMP)-activated protein kinase (AMPK), Farnesoid X receptor (FXR) and retinoic acid receptor (RAR), and protein expression of phospho-acetyl CoA carboxylase (p-ACC) were evaluated. ResultsA significant amelioration was noticed in serum liver indices, lipid profile, liver histopathology, body weight gain, and p-ACC/ACC protein expression in both FE and DSG treated groups compared to the NASH untreated group. DSG-treated groups significantly (p<0.05) decreased serum glucose levels and HOMA-IR compared to the NASH untreated group. FE significantly upregulated AMPK compared to the NASH untreated group and DSG-treated groups. However, RAR downregulation and FXR overexpression of the NASH group were not normalized in treated groups. ConclusionThis study proved that FE and DSG both protected the liver against NASH. The DSG impact was dose-dependent. However, the activation of the AMPK cascade was believed to be the mechanism by which FE exerted its hepatoprotective effects.

The interaction of T2DM and BMI with NASH in recipients of liver transplants: an SRTR database analysis

ABSTRACT Background NASH-related liver transplants are increasing because of the obesity epidemic, but the influence of T2DM on various levels of BMI among NASH recipients is unclear. Research design and methods We analyzed data retrieved from SRTR on 4,515 patients. We divided patients by BMI into five groups: normal weight; overweight; class 1 obesity; class 2 obesity; and class 3 obesity. Statistical analysis was done. Results Patients in the NASH group with T2DM had a lower patient and graft survival than patients without T2DM (5-year patient and graft survival: 77.5% vs. 79.8%; P = 0.001 and 76.4% vs. 78.2%; P = 0.002, respectively). Multivariate Cox proportional regression showed an independent association between T2DM and decreased patient and graft survival (HR, 1.170; P = 0.015 and HR, 1.133; P = 0.048, respectively). In the lean and the class 3 obesity NASH groups, patients with T2DM had lower patient and graft survival than the patients without T2DM. In the class 3 obesity NASH group, T2DM was independently associated with decreased patient survival (HR, 1.581; P = 0.027). Conclusion Our research reveals that the focus of the post-transplantation treatment should be different for different BMI patients.

Biomarkers in Determining the Risk of Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Hypertension

IntroductionNon-alcoholic steatohepatitis (NASH) affects up to 50% of patients with arterial hypertension (HT). Laboratory biomarkers are believed to help in liver fibrosis (LF) risk determination in patients with NASH and HT. PurposeTo assess the kallistatin, IL-10, IL-1β and high-sensitivity CRP (hsCRP) significance in LF risk evaluation in patients with NASH and HT. Methods. 63 patients with NASH and HT and 52 patients with isolated NASH were examined. Plasma kallistatin, IL-10, IL-1β and hsCRP levels were evaluate using ELISA. The results were statistically processed with the ROC analysis, the area under ROC curve (AUC), sensitivity (SE) and specificity (SP) were determined. ResultsKallistatin showed excellent diagnostic characteristics for LF development and progression risk determination in patients with NASH and HT (AUC=0.975, p=0.003, SE=95%, SP=100%; AUC=0.881, p<0.001; SE=95%, SP=76.9%) and isolated NASH (AUC=0.867, p<0.001); SE=76.5%, SP=81.0%; AUC=0.889, p<0.001, SE=92.3%, SP=81.3%). Interleukins showed good diagnostic characteristics for LF development risk in both groups (IL-10: AUC=0.769, p=0.012, SE=70%, SP=64.1%; AUC=0.710, p=0.009, SE=94.4%, SP=69.2%, IL 1β: AUC=0.752, p=0.02, SE=71.8%, SP=75.0%, AUC=0.788, p=0.007, SE= 84.6%, SP=66.7%), hsCRP showed diagnostical potential only in NASH and HT patients (AUC=0.849, p<0.001, SE=71.8%; SP=75.0%). Simultaneous evaluation of all biomarkers showed excellent and very good diagnostic characteristics for LF development and progression risk determination in NASH and HT patients (AUC=1.000, SE=100%, SP=100%, p=0.002; AUC=0.874, SE=82.1%, SP=85.0%, p<0.001) and isolated NASH group (AUC=0.874, SE=94.1%, SP=71.4%, p<0.001; AUC=0.889, SE=84.6%, SP=94.4%, p<0.001). ConclusionsThis allows us to offer kallistatin, IL-10, IL-1β, and hsCRP combination for LF identification in patients with NASH and HT.

Abstract 15512: The Hepatic Lipid Type and Content Had an Impact on Hepatic Inflammation and Fibrosis in Streptozotocin-Induced Diabetic Mice

Introduction: It has been reported that nonalcoholic fatty liver disease is an independent risk factor for cardiovascular diseases. We have recently demonstrated that diet-induced steatohepatitis was associated with cardiac dysfunction and those were improved by the selective PPARα modulator, pemafibrate in wild type mice. Hypothesis: The aim of the study is to characterize the relationship between hepatic lipid content and inflammation, induced by two type of diets in diabetic mice model and to test the effect of pemafibrate on those. Methods: C57BL/6 mice were injected with streptozotocin (STZ) (40mg/kg for 4 days). Mice whose ad libitum blood glucose were 200-350mg/dl, were used as diabetic mice. In 11-week-old STZ induced diabetic mice were administered wild high fat/high cholesterol diet (WD group) or high fat/high cholesterol/ high sucrose/bile acids diet (NASH group), with or without pemafibrate for 12 weeks. Lipid profiles, liver cytokines, hepatic mRNA, liver histology were investigated. Results: Total cholesterol and unesterified cholesterol were significantly more accumulated in the NASH group compared to the WD group. Triglyceride were not changed between two groups. F4/80 positive area and sirius-red positive area were significantly increased in the NASH group compared to the WD group. Inflammatory cytokines such as Tnfa, Il1b and fibrosis associated genes Col1a1 and Col1a2 were also significantly increased in the NASH group, suggesting the presence of active inflammation and fibrosis in the NASH group. By co-administration with pemafibrate, serum HDL-C level was increased by 48.7% and the non-HDL-C level was decreased by 31.4% in the NASH/pemafibrate group. Importantly, total cholesterol and unesterified cholesterol were markedly decreased in the NASH/pemafibrate group. Along with those, F4/80 positive area and sirius-red positive area were decreased in the NASH/pemafibrate group by more than 50%. Hepatic Tnfa expression was decreased by 56.3% and Tgfb, Col1a1, Col1a2 was significantly decreased. Conclusions: Our study demonstrated that more total cholesterol and unesterified accumulation induced hepatic inflammatory responses and fibrosis in the diabetic mice and pemafibrate had the beneficial impacts on those.

Does size matter in group decision making? Simulation experiments with LNG professionals bidding in auction markets

Purpose: An important issue in decision-making processes is whether groups decide better than individuals. This paper compares the bidding behavior of groups of professionals while playing a business game that simulates, in a controlled environment, the sequential unit capacity auctions in the Spanish LNG market.Design/methodology/approach: First, we randomly grouped professionals in groups of different size—SOLOs, DUOs, and TRIOs—and played the game in-situ under both First and Second price unit capacity auctions, with SOLOs outperforming groups. Second, we ran non-parametric simulations mixing professionals in groups of different size, in which bids were coupled with those registered during the in-situ sessions. Third, we ran non-parametric simulations in which the players were either ‘rational machines’ that bid according to Nash equilibrium or groups of ‘professionals’ of different size.Findings: The size of the decision group does matter. After the in-situ and the bootstrapped simulated games, the main result is that size does matter, and groups are not necessarily superior to individuals bidding alone. SOLO players bid closer to MACHINEs and lower than DUOs or TRIOs, while obtaining about the same number of units and higher payoffs than groups. Additionally, the ‘degree of rationality’ of the participants does also matter.Research limitations/implications: Even after applying the hybrid simulation methodology to increase sample size and allow for additional experimental settings, some of the scenarios are fictitious. Modification of the business game to allow for an even more realistic game could be implemented.Practical implications: After the hybrid simulation approach, the main implication of the paper is that to increase efficiency in resource allocation professionals should bid individually while using the theoretical knowledge of rational machines.Originality/value: To our knowledge, this is the first time that this double-experiment simulation methodology is used to analyze bidding behavior in auctions.

Effect of Liraglutide on Serum TSH Levels in Patients with NAFLD and its Underlying Mechanisms.

This study aimed to evaluate the effect of liraglutide on serum thyroid-stimulating hormone (TSH) levels in patients with type 2 diabetes mellitus (T2DM) and explore the underlying mechanisms via bioinformatics analysis. A total of 49 obese/overweight patients with T2DM received liraglutide during outpatient visits or hospitalization in the Department of Endocrinology. Meanwhile, the control group included 49 patients with T2DM but without nonalcoholic fatty liver disease (NAFLD) who were matched for age and sex (baseline from July 2016 to June 2021). Follow-up data on the last use of liraglutide were also retrieved. Age, sex, body mass index (BMI), and duration of diabetes were obtained from the participants' records. All patients were tested for biochemical markers hemoglobin A1c (HbA1c), alanine transaminase, aspartate transaminase, free triiodothyronine, free thyroxine (FT4), and TSH at baseline and follow-up. After adjusting for all factors with a p-value < 0.05, BMI, HbA1c, LDL, FT4, and TSH were identified as significant independent risk factors for NAFLD in the univariate analysis. Following liraglutide therapy (average time 16 months), these patients had significantly lower BMI, HbA1c, and TSH but higher high-density lipoprotein (HDL) levels than those in the baseline data (all p < 0.05), and further subgroup analysis stratified by duration of liraglutide use showed that the test for time trends had statistical differences in BMI and TSH but not in HbA1c and HDL. After the therapy, the NAFLD and NASH groups showed significantly decreased TSH levels after liraglutide therapy compared with the corresponding baseline data. Furthermore, the expression of THRB, which encodes TRβ, was significantly decreased in the NAFLD group, which may explain the thyroid hormone resistance-like manifestation in the clinical findings. In conclusion, liraglutide improves hepatic thyroid hormone resistance in T2DM with NAFLD, and restoration of impaired TRβ expression in NAFLD is a potential mechanism involved in the process of liraglutide therapy.

New roles of N6-methyladenosine methylation system regulating the occurrence of non-alcoholic fatty liver disease with N6-methyladenosine-modified MYC.

Non-alcoholic fatty liver disease (NAFLD) has become a major chronic disease in contemporary society, affected by N6-methyladenosine (m6A) RNA methylation, one of the most common RNA modifications. Compared with healthy control, m6A RNA methyltransferase 3 (METTL3) and METTL14 increased, while Wilms tumor 1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15) decreased significantly in NAFLD, and the m6A demethylases fat mass and obesity-associated protein (FTO) elevated. Meanwhile, the m6A binding proteins, YT521-B homology (YTH) domain-containing 1 (YTHDC1), YTHDC2, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), and HNRNPA2B1 were decreased, while eukaryotic translation initiation factor 3 subunit H (EIF3H) was increased significantly. All these changes of m6A regulators had significant differences between healthy control and NAFLD, but no differences between the NAFL and NASH group. The expression level of RBM15, HNRNPC, and HNRNPA2B1 were related to body fat index. RBM15, YTHDC2, HNRNPC, HNRNPA2B1, and EIF3H were related to steatosis. Also, KIAA1429 and YTH domain family 1 (YTHDF1) were related to lobular inflammation. Taken together, m6A regulators were involved in the occurrence of NAFLD. More importantly, abnormal MYC was determined as a key link to m6A regulation of NAFLD. The higher MYC mRNA level was accompanied by higher HDL cholesterol and unsaturated fatty acid proportions, as well as lower fat mass, glucose, and transaminase. Taken together, dysregulation of m6A methylation caused steatosis and fibrosis, affecting the occurrence of NAFLD, and MYC might be its potential target.

Classification of connected commutative locally Nash groups

In this article, we classify connected commutative (locally) Nash groups, which is a continuation of our previous work on the classification of abelian Nash manifolds. Our results generalize the classification of the one-dimensional case by Madden-Stanton and the two-dimensional case by Baro-Vicente-Otero. Moreover, we determine the affineness and toroidal affineness of a connected commutative Nash group.