Nonalcoholic Steatohepatitis Patients Research Articles

Shared biomarkers and immune cell infiltration signatures in ulcerative colitis and nonalcoholic steatohepatitis

The coexistence of ulcerative colitis (UC) and nonalcoholic steatohepatitis (NASH) involves a intricate interplay, though the precise pathophysiological mechanisms remain elusive. To shed light on this, our study endeavors to unravel the shared gene signatures and molecular mechanisms by employing quantitative bioinformatics analysis on a publicly available RNA-sequencing database. Gene expression profiles of UC (GSE87466) and NASH (GSE89632) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using R software. After identifying common DEGs, functional enrichment analysis, protein–protein interaction (PPI) network analysis and module construction were performed to obtain candidate hub genes. GSE47908 for UC and GSE159676 for NASH were selected to validate the obtained candidate genes. A total of 119 common DEGs were found in NASH and UC patients. Functional and pathway analyses emphasized that viral infection, inflammation and immune response were enriched in these two diseases. After module construction and validation, CD2, CD8A, GNLY, IFI44, NKG7 and OAS2 were identified as hub genes. 6 hub genes and their combined prediction scores were found with an impressive accuracy and sensitivity. Functional estimation, gene set enrichment analysis and immune infiltration signature identification showed notable associations of the six hub genes with T cells, natural killer cells and type I interferon levels. In addition, we constructed UC combined with NASH mice model successfully with significantly higher expression of hub genes in both liver and colonic tissues than those in control group. Our study elucidates 6 hub genes of UC and NASH, which may participate in immune, inflammatory and antiviral effects. These findings provide some potential biochemical markers for further exploration of UC coexistence with NASH.

Prospects of using sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with metabolic-associated fatty liver disease (MAFLD)

Metabolic dysfunction-associated fatty liver disease (MAFLD) is recognised worldwide as a serious health problem, given the global prevalence of about 30% of the world population and high incidence of nonalcoholic steatohepatitis (NASH), which has reached epidemic levels in the 12%-21% of people with type 2 diabetes mellitus (DM). In patients with comorbidity of type 2 DM, atherosclerotic cardiovascular disease (ASCVD), visceral obesity (VO), insulin resistance syndrome (IRS) the frequency of MAFLD is 70%. For this reason a modern, complex and patient-oriented approach to the treatment of MAFLD is of paramount importance, which can simultaneously treat several disorders by preventing interaction between underlying causes of NASH in patients with type 2 DM. The growing burden of morbidity, therapeutic inertia of primary care physicians and highly specialized gastroenterologists, endocrinologists regarding early diagnostics of NASH in people with type 2 DM and VO often leads to incomplete treatment of MAFLD manifestations. Nowadays SGLT-2 inhibitors present an innovative class of hypoglycemic drugs which have improved the glucose-centric approach to the therapy of type 2 DM combined with organ-protective properties. The data obtained from epoch-making controlled clinical trials and clinical practice presents an opportunity of new clinical horizons regarding the hepatoprotective properties of SGLT-2 inhibitors. In this review the efficacy, safety and prospects of using SGLT-2 in patients with MAFLD were evaluated.

Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH. We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay. Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80. A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.

MicroRNA-582-3p knockdown alleviates non-alcoholic steatohepatitis by altering the gut microbiota composition and moderating TMBIM1.

The gut dysbiosis correlates with non-alcoholic steatohepatitis (NASH), involving the moderation of miRNAs. This study was aimed to investigate the correlation between gut microbiota and miR-582-3p in patients with non-alcoholic steatohepatitis (NASH) and to explore the possible regulation of miR-582-3p in the function of the activated hepatic stellate cells (HSCs). GSE69670 and GSE14435 datasets were analyzed by GEO2R. Plasma and fecal samples were obtained from the subjects, non-steatosis (n = 35), simple steatosis (n = 35), and NASH (n = 35). The variations in intestinal microbiota in the non-steatosis and NASH groups were analyzed using 16S rRNA sequencing. The expression of miR-582-3p among the groups was detected using RT-qPCR. Correlations between top-changed intestinal microbiota and miR-582-3p expression were analyzed using the Pearson correlation coefficient. Target gene identification was performed by prediction and dual-luciferase reporter assay. The effect of miR-582-3p on the cell function of TGF-β1-induced HSCs was assessed in vitro. miR-582-3p was the common differentially expressed miRNA between GSE69670 and GSE14435. miR-582-3p was upregulated in NASH patients' plasma, as well as in TGF-β1-induced LX-2 cells. The non-steatosis and NASH groups showed significantly different intestinal microbiota distribution. miR-582-3p was positively correlated with specific microbiota populations. TMBIM1 was a target gene for miR-582-3p. Knockdown of miR-582-3p suppressed HSC proliferation and myofibroblast markers' expression but induced cell apoptosis, via TMBIM1. This present study suggests that miR-582-3p promotes the progression of NASH. Knockdown of miR-582-3p may alleviate NASH by altering the gut microbiota composition and moderating TMBIM1.

S1588 Prevalence and Risk Factors Associated With Non-Alcoholic Steatohepatitis in Patients With Helicobacter pylori Infection: A Population-Based Study

S1588 Prevalence and Risk Factors Associated With Non-Alcoholic Steatohepatitis in Patients With Helicobacter pylori Infection: A Population-Based Study

S1509 Prevalence of Non-Alcoholic Steatohepatitis in Patients with Cholelithiasis and Fatty Liver: Is Routine Liver Biopsy Necessary?

S1509 Prevalence of Non-Alcoholic Steatohepatitis in Patients with Cholelithiasis and Fatty Liver: Is Routine Liver Biopsy Necessary?

S1436 Prevalence and Risk Factors Associated With Non-Alcoholic Steatohepatitis in Patients With Rheumatoid Arthritis on Hydroxychloroquine: A Population-Based Study

S1436 Prevalence and Risk Factors Associated With Non-Alcoholic Steatohepatitis in Patients With Rheumatoid Arthritis on Hydroxychloroquine: A Population-Based Study

S1297 Trends in Indications and Outcomes for Endoscopic Retrograde Cholangiopancreatography in Non-Alcoholic Steatohepatitis Patients

S1297 Trends in Indications and Outcomes for Endoscopic Retrograde Cholangiopancreatography in Non-Alcoholic Steatohepatitis Patients

Assessing the diagnostic value of zonulin as a biomarker for intestinal permeability in patients with metabolic-associated fatty liver disease in combination with type 2 diabetes mellitus

The aim of the study was to assess the diagnostic value of serum zonulin concentrations in patients with metabolic-associated fatty liver disease (МAFLD) in combination with type 2 diabetes mellitus (T2DM). Materials and methods. The study involved 93 patients with MAFLD in combination with T2DM, who were examined and allocated to two groups. Group 1 consisted of 48 patients with non-alcoholic steatohepatitis (NASH) in combination with T2DM without small intestinal bacterial overgrowth (SIBO) syndrome. Group 2 comprised 45 patients with NASH in combination with T2DM and SIBO. The control group consisted of 25 apparently healthy persons. The ELISA method was used for quantitative determination of serum zonulin. Results. When comparing parameters of liver functional activity and ultrasonographic findings of liver steatosis and fibrosis, a significant increase in the activity of ALT and AST was revealed in Group 1 – 67.22 ± 2.25 U/l and 52.97 ± 1.04 U/l (p < 0.001) and in Group 2 – 69.20 ± 1.52 U/l and 54.82 ± 1.10 U/l (p < 0.001) compared to those in the control group – 18.00 ± 1.01 U/l and 18.96 ± 0.82 U/l (p < 0.001) respectively, as well as an increase in the ultrasound attenuation coefficient (UAC) in patients of Groups 1 and 2 amounting to 2.94 ± 0.03 dB/cm and 2.92 ± 0.04 dB/cm, respectively, and also the liver stiffness (LS) in Group 1 – 8.06 ± 0.07 kPa and in Group 2 – 8.00 ± 0.06 kPa compared to those in the control group (p < 0.001). When measuring the level of serum zonulin, a significant increase was revealed in patients of Group 1 – 61.69 ± 1.04 ng/ml and Group 2 – 89.39 ± 1.30 ng/ml compared to that in the control group – 16.76 ± 1.47 ng/ml (p < 0.001). Analyzing correlation coefficients in patients of Groups 1 and 2, a positive linear moderate association was found between the serum zonulin concentration and the activity of ALT, AST and UAC and LS. Conclusions. The study resultsobtained have demonstrated the great diagnostic value of serum zonulin as a biomarker of intestinal permeability in NASH patients in combination with T2DM, and with or without SIBO.

Hepatocytic Ballooning in Non-alcoholic Steatohepatitis: Bridging the Knowledge Gap and Charting Future Avenues.

Non-alcoholic steatohepatitis (NASH) is emerging as a significant global health concern, characterized by hepatic lipid accumulation, inflammation, and hepatocellular injury. Hepatocytic ballooning, a histological feature of NASH, has gained prominence for its role in disease progression and potential as a therapeutic target. This review provides an overview of the current knowledge regarding hepatocytic ballooning in NASH, highlighting the key molecular and cellular mechanisms implicated in its development. We delve into the intricate interplay of metabolic dysregulation, oxidative stress, and lipid toxicity as drivers of hepatocytic ballooning, shedding light on the pathways responsible for its initiation and perpetuation. Furthermore, we explore the diagnostic challenges associated with hepatocytic ballooning and its significance as a prognostic indicator in NASH patients. While hepatocytic ballooning holds promise as a therapeutic target, this abstract discusses the various experimental and clinical approaches to ameliorate this histological hallmark. Potential interventions, including lifestyle modifications, pharmacological agents, and emerging therapies, are evaluated in terms of their efficacy and safety profiles. In conclusion, this review underscores the need to bridge the knowledge gap surrounding hepatocytic ballooning in NASH and emphasizes its importance in understanding disease pathogenesis and progression. By charting future research avenues and clinical strategies, we aspire to advance our comprehension of NASH and ultimately improve patient outcomes in this rapidly evolving field of hepatology.

Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy

ObjectiveAbnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. MethodsExpression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. ResultsAutophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet–fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. ConclusionsCollectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy.

Mortality and Cardiovascular Outcomes in Adult Non-Liver Solid Organ Transplant Patients With Nonalcoholic Steatohepatitis

The effect of nonalcoholic steatohepatitis (NASH) on mortality or major adverse cardiovascular events (MACE) in non-liver solid organ transplant recipients (NL-SOT) is unknown. Using a retrospective design, adult NL-SOT recipients who had biopsy-proven NASH were compared NL-SOT recipients with normal liver function tests and imaging; propensity matched at a 1:10 ratio on the following: age, sex, race, transplant year, transplant organ, smoking status, and diabetes status. Both deceased and living donor recipients were included; heart and liver transplant patients were excluded. Primary outcome was incidence of all-cause mortality and MACE (a composite outcome of coronary artery disease, ischemic stroke, and peripheral arterial disease). Seven patients (3 kidney and 4 lung transplants) had biopsy-proven NASH and 70 patients without NASH, both groups were predominantly male (53%-57%), White (86%-91%), and overweight (mean body mass index ∼ 26). The majority of patients were on calcineurin inhibitors (≥85%), antimetabolites (≥97%), and prednisone (≥50%). Survival analysis showed that NASH patients had a higher risk of death (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.26-8.33, P=0.02). NASH did not affect the risk of death-censored graft failure (HR, 1.08; 95% CI, 0.14-8.67; P=.94) or the risk of MACE (HR, 1.03; 95% CI, 0.23-4.62; P=.97). In NL-SOT recipients, NASH is significantly associated with mortality but not with MACE.

Elucidating Cuproptosis-Associated Genes in the Progression from Nash to HCC Using Bulk and Single-Cell RNA Sequencing Analyses and Experimental Validation.

Background and Objectives: Non-alcoholic steatohepatitis (NASH) is a significant risk factor for hepatocellular carcinoma (HCC) development. Timely treatment during the NASH stage is essential to minimize the possibility of disease progression to HCC. Cuproptosis is a newly identified form of cellular death that could impact the progression of various diseases and cancers. Materials and Methods: Transcriptome and single-cell sequencing datasets were utilized to investigate the role of cuproptosis-related genes (CRGs) in NASH progression to HCC. FDX1, LIPT1, and PDHP were identified as CRGs in NASH patients, and FDX1, DBT, GCSH, SLC31A1, and DLAT were identified as CRGs in patients with NASH progressing to HCC. FDX1 was found to play a significant role in both NASH patients and patients with NASH progressing to HCC. This study constructed cuproptosis-related clusters (CRCs) using the Nonnegative Matrix Factorization algorithm, and they were linked to fatty acid metabolism and the PPAR signaling pathway in both NASH CRCs and HCC CRCs. The Weighted Correlation Network Analysis algorithm identified CRP, CRC, TAT, CXCL10, and ACTA1 as highly relevant genes in NASH CRCs and HCC CRCs. The expression of FDX1 was validated in both mouse models and human NASH samples. Results: The investigation highlights FDX1 as a pivotal CRG in both NASH and NASH progression to HCC. The comprehensive characterization of CRGs sheds light on their potential biofunctional importance in the context of NASH and HCC. Our experimental results show that FDX1 expression was significantly increased in NASH patients. Conclusions: The present study identified key CRGs, revealing their potential impact on NASH and HCC. Meanwhile, targeting FDX1 may prevent the progression of NASH to HCC.

MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.

Mediator subunit MED1 deficiency prevents carbon tetrachloride-induced hepatic fibrosis in mice.

Mediator subunit mediator 1 (MED1) mediates ligand-dependent binding of the mediator coactivator complex to various nuclear receptors and plays a critical role in embryonic development, lipid and glucose metabolism, liver regeneration, and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice and positively correlated with transforming growth factor β (TGF-β) signaling and profibrotic factors. Upon treatment with carbon tetrachloride (CCl4), hepatic fibrosis was much less in liver-specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-β/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 α 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-administered MED1ΔLiv mice were enriched in the pathway of oxidoreductase activity, followed by robustly reduced oxidoreductase activity-related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that the reduction of reactive oxygen species (ROS) in MED1 knockdown hepatocytes blocked the activation of TGF-β/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.NEW & NOTEWORTHY In this study, we present the first evidence that liver mediator 1 (MED1) deficiency attenuated carbon tetrachloride-induced hepatic fibrosis in mouse. The underlying mechanism is that MED1 deficiency reduces reactive oxygen species (ROS) production in hepatocytes, thus restricts the activation of TGF-β/Smad2/3 signaling pathway and fibrogenic genes expression in hepatic stellate cells (HSCs). These data suggest that MED1 is an essential regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for liver fibrosis.

Role of Activin A as a Novel Marker for Diagnosis and Evaluation of Nonalchoholic Fatty Liver Disease

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a disease gaining increasing interest worldwide. It ranges from simple nonalcoholic steatosis to nonalcoholic steatohepatitis (NASH), is characterized by steatosis, inflammation and fibrosis, and may lead to liver cirrhosis and hepatocellular carcinoma. Nonalcoholic fatty liver disease shares common pathogenetic mechanisms with other components of the insulin resistance or metabolic syndrome, with adipokines playing a crucial role. Aim of the Work Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD). Patients and Methods This study is a comparative case control study. This study was carried out at outpatient’s clinics of internal medicine department of Ain Shams University. Target population Group 1: Including 35 patients with NAS (steatosis) with exclusion criteria of intake of hepatotoxic drugs. Group 2: Including 35 patients with fatty liver and elevated liver enzymes (NASH). Group 3: Including 20 patients as a control group. Results There was high statistically significant difference between the studied groups as regard weight and BMI. In the Steatosis group the mean Liver size was 13.97 (±1.29 SD) with range (1216) cm, all the patients (100%) had enlarged- echogenic liver. In the NASH group the mean Liver size was 13.71 (±1.36 SD) with range (12-16) cm, all the patients (100%) had enlarged-echogenic liver. In the control group the mean Liver size was 9.85 (±1.5 SD) with range (8-12) cm, all the patients (100%) had Normal liver. There was high statistically significant difference between the studied groups as regard liver size. There was high statistically significant difference between the studied groups as regard ALT, AST, total and direct bilirubin, plts count and activin A, significant difference between the studied groups as regard Albumin. There was high statistically significant difference between the studied groups as regard APRI score, FIB-4. There was high correlation between Activin A and BMI, APRI score, FIB-4 and liver size with high significance (p < 0.001). Using Activin A. it was shown that above 858.5, it can discriminate between NAFLD and nonNAFLD with level of sensitivity 100% and specificity 100%. Conclusion Serum activin A showed a trend towards progressive increase from controls, to SS and NASH patients, but the significance was lost after adjustment for measures of adiposity. Activin A was not independently associated with NASH or any specific hepatic lesion within NAFLD patients. Prospective studies are needed to confirm the hypothesis raised herein, before mechanistic studies attempt to elucidate mechanism and prove causality.

Non Invasive Biomarkers for Non-Alcoholic Fatty Liver Disease in Egyptian Obese Patients Undergoing Bariatric Surgeries

Background Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the worldwide occurring in 33 % of the general population and in over 90% of the patients with morbid obesity that are undergoing bariatric surgery. NAFLD encompasses a histological spectrum ranging from simple steatosis (NAFLD) to nonalcoholic steatohepatitis (NASH) with various degrees of fibrosis that may progress eventually to cirrhosis. A key issue for the prognosis and management of NAFLD is the differentiation of simple steatosis from NASH. To date, liver biopsy remains the best gold standard for diagnosing NASH and grading the severity of liver damages but it is invasive procedure. There is an urgent need for a less invasive method than biopsy of screening the population, stratifying disease severity and following disease progression. Aim of the Work To evaluate promising non-invasive predictive biomarkers used to distinguish between NASH and simple steatosis in morbidly obese patients undergoing bariatric surgery. Patients and Methods This was a case control study conducted in morbidly obese patients before they had gone bariatric surgery between January 2018 and January 2020 with a total number of 30 patients. We included morbidly obese patients (BMI≥40 kg/m²) undergoing bariatric surgeries. Liver biopsies were obtained at time of bariatric surgery and examined by single pathologist and graded according to NAFLD activity score (NAS), Results This study was conducted on 30 patients who were morbidly obese before they had gone bariatric surgery at Ain Shams University Hospitals. Among the 30 patients, 21 of them diagnosed as NASH by the liver biopsy, 42.9% of the NASH patients were diabetic, and 47.6% of them were hypertensive. The BMI and hip circumference were highly significant with NASH with cut off level of BMI >42.6 and 85.71% sensitivity and 66.67% specificity. Using AUC analysis, we established for these parameters the following cutoff levels being indicative of NASH with the highest accuracy (equal or above): BMI of 42.6 kg/m2, HOMAIR of > 3.6. For adiponectin, a value equal or below 2.9 mg/L was indicative of NASH and hs-CRP of above 1.5 mg/L. Conclusion BMI> 42.6 kg/m², HOMA-IR, adiponectin, hs-CRP are good non- invasive indicators for NASH in morbidly obese patients undergoing bariatric surgeries.

Gossypetin prevents the progression of nonalcoholic steatohepatitis by regulating oxidative stress and AMP-activated protein kinase.

Nonalcoholic steatohepatitis (NASH) is severe liver metabolic disorder, however, there are still no effective and safe drugs for its treatment. Previous clinical trials used various therapeutic approaches to target individual pathological mechanisms, but these approaches were unsuccessful because of the complex pathological causes of NASH. Combinatory therapy in which two or more drugs are administered simultaneously to patients with NASH, however, it carries the risk of side effects associated with each individual drug. To solve this problem, we identified gossypetin as an effective dual-targeting agent that activates AMP-activated protein kinase (AMPK) and decreases oxidative stress. Administration of gossypetin decreased hepatic steatosis, lobular inflammation and liver fibrosis in the liver tissue of mice with CDHFD and MCD diet-induced NASH. Gossypetin functioned directly as anti-oxidant agents, decreasing hydrogen peroxide and palmitate-induced oxidative stress in the AML12 cells and liver tissue of MCD diet fed mice without regulating the antioxidant response factors. In addition, gossypetin acted as a novel AMPK activator by binding to the allosteric drug and metabolite (ADaM) site, which stabilizes the activated structure of AMPK. Our findings demonstrate that gossypetin has the potential to serve as a novel therapeutic agent for NAFLD/NASH. Significance Statement This study demonstrates that gossypetin has preventive effect to progression of NASH as a novel AMPK activator and antioxidants. Our findings implicate that simultaneous activation of AMPK and oxidative stress using gossypetin has the potential to serve as a novel therapeutic approach for NAFLD/NASH patients.

Production, Exacerbating Effect, and EV-Mediated Transcription of Hepatic CCN2 in NASH: Implications for Diagnosis and Therapy of NASH Fibrosis.

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, hepatocyte ballooning, and inflammation and may progress to include increasingly severe fibrosis, which portends more serious disease and is predictive of patient mortality. Diagnostic and therapeutic options for NASH fibrosis are limited, and the underlying fibrogenic pathways are under-explored. Cell communication network factor 2 (CCN2) is a well-characterized pro-fibrotic molecule, but its production in and contribution to NASH fibrosis requires further study. Hepatic CCN2 expression was significantly induced in NASH patients with F3-F4 fibrosis and was positively correlated with hepatic Col1A1, Col1A2, Col3A1, or αSMA expression. When wild-type (WT) or transgenic (TG) Swiss mice expressing enhanced green fluorescent protein (EGFP) under the control of the CCN2 promoter were fed up to 7 weeks with control or choline-deficient, amino-acid-defined diet with high (60%) fat (CDAA-HF), the resulting NASH-like hepatic pathology included a profound increase in CCN2 or EGFP immunoreactivity in activated hepatic stellate cells (HSC) and in fibroblasts and smooth muscle cells of the vasculature, with little or no induction of CCN2 in other liver cell types. In the context of CDAA-HF diet-induced NASH, Balb/c TG mice expressing human CCN2 under the control of the albumin promoter exhibited exacerbated deposition of interstitial hepatic collagen and activated HSC compared to WT mice. In vitro, palmitic acid-treated hepatocytes produced extracellular vesicles (EVs) that induced CCN2, Col1A1, and αSMA in HSC. Hepatic CCN2 may aid the assessment of NASH fibrosis severity and, together with pro-fibrogenic EVs, is a therapeutic target for reducing NASH fibrosis.

Plasma Lipids Profile in the Prediction of Non-Alcoholic Steatohepatitis in Adults: A Case-Control Study.

Patients with non-alcoholic steatohepatitis (NASH) show significantly faster progress in the stages of fibrosis compared to those with non-alcoholic fatty liver (NAFL) disease. The non-invasive diagnosis of NASH remains an unmet clinical need. Preliminary data have shown that sphingolipids, especially ceramides, fatty acids, and other lipid classes may be related to the presence of NASH and the histological activity of the disease. The aim of our study was to assess the association of certain plasma lipid classes, such as fatty acids, acylcarnitines, and ceramides, with the histopathological findings in patients with NASH. The study included three groups: patients with NASH (N = 12), NAFL (N = 10), and healthy [non non-alcoholic fatty liver disease (NAFLD)] controls (N = 15). Plasma samples were collected after 12 h of fasting, and targeted analyses for fatty acids, acylcarnitines, and ceramides were performed. Baseline clinical and demographic characteristics were collected. There was no significant difference in baseline characteristics across the three groups or between NAFL and NASH patients. Patients with NASH had increased levels of several fatty acids, including, among others, fatty acid (FA) 14:0, FA 15:0, FA 18:0, FA 18:3n3, as well as Cer(d18:1/16:0), compared to NAFL patients and healthy controls. No significant difference was found between NAFL patients and healthy controls. In conclusion, patients with NASH exhibited a distinctive plasma lipid profile that can differentiate them from NAFL patients and non-NAFLD populations. More data from larger cohorts are needed to validate these findings and examine possible implications for diagnostic and management strategies of the disease.