Nonalcoholic Steatohepatitis Patients Research Articles

Role of resmetirom, a liver-directed, thyroid hormone receptor beta-selective agonist, in managing non-alcoholic steatohepatitis: a systematic review and meta-analysis

Role of resmetirom, a liver-directed, thyroid hormone receptor beta-selective agonist, in managing non-alcoholic steatohepatitis: a systematic review and meta-analysis

HSD17B13 liquid-liquid phase separation promotes leukocyte adhesion in chronic liver inflammation.

The rs72613567:TA polymorphism in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) has been found to reduce the progression from steatosis to nonalcoholic steatohepatitis. In this study, we sought to define the pathogenic role of HSD17B13 in triggering liver inflammation. Here we find that HSD17B13 forms liquid-liquid phase separation (LLPS) around lipid droplets in the livers of nonalcoholic steatohepatitis patients. The dimerization of HSD17B13 supports the LLPS formation and promotes its enzymatic function. HSD17B13 LLPS increases the biosynthesis of platelet activating factor (PAF), which in turn promotes fibrinogen synthesis and leukocyte adhesion. Blockade of PAFR or STAT3 pathway inhibited the fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated viral-mediated xeno-expression of human HSD17B13 exacerbated western diet/carbon tetrachloride-induced liver inflammation in Hsd17b13-/- mice. In conclusion, our results suggest that HSD17B13 LLPS triggers liver inflammation by promoting PAF-mediated leukocyte adhesion, and targeting HSD17B13 phase transition could be a promising therapeutic approach for treating hepatic inflammation in chronic liver disease.

A Systematic Review of Statins for the Treatment of Nonalcoholic Steatohepatitis: Safety, Efficacy, and Mechanism of Action.

Nonalcoholic fatty liver disease (NAFLD) is the liver component of a cluster of conditions, while its subtype, nonalcoholic steatohepatitis (NASH), emerges as a potentially progressive liver disorder that harbors the risk of evolving into cirrhosis and culminating in hepatocellular carcinoma (HCC). NASH and cardiovascular disease (CVD) have common risk factors, but compared to liver-related causes, the most common cause of death in NASH patients is CVD. Within the pharmacological armamentarium, statins, celebrated for their lipid-modulating prowess, have now garnered attention for their expansive therapeutic potential in NASH. Evidence from a plethora of studies suggests that statins not only manifest anti-inflammatory and antifibrotic properties but also impart a multifaceted beneficial impact on hepatic health. In this review, we used "statin", "NAFLD", "NASH", and "CVD" as the major keywords and conducted a literature search using the PubMed and Web of Science databases to determine the safety and efficacy of statins in patients and animals with NASH and NAFLD, and the mechanism of statin therapy for NASH. Simultaneously, we reviewed the important role of the intestinal microbiota in statin therapy for NASH, as it is hoped that statins will provide new insights into modulating the harmful inflammatory microbiota in the gut and reducing systemic inflammation in NASH patients.

O-GlcNAcylation promotes the progression of nonalcoholic fatty liver disease by upregulating the expression and function of CD36

Background and aimsNonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH), constitute a burgeoning worldwide epidemic with no FDA-approved pharmacotherapies. The multifunctional immunometabolic receptor, fatty acid translocase CD36 (CD36), plays an important role in the progression of hepatic steatosis. O-GlcNAcylation is a crucial posttranslational modification that mediates the distribution and function of CD36, but its involvement in NAFLD remains poorly understood. MethodsO-GlcNAcylation and CD36 expression were evaluated in human liver tissues obtained from NASH patients and normal control. Mice with hepatocyte-specific CD36 knockout were administered adeno-associated viral vectors expressing wild-type CD36 (WT-CD36) or CD36 O-GlcNAcylation site mutants (S468A&T470A-CD36) and were provided with a high-fat/high-cholesterol (HFHC) diet for 3 months. RT–qPCR analysis, immunoblotting, dual-luciferase reporter assays, chromatin immunoprecipitation, and coimmunoprecipitation were performed to explore the mechanisms by which O-GlcNAcylation regulates CD36 expression. Membrane protein extraction, immunofluorescence analysis, site-directed mutagenesis, and fatty acid uptake assays were conducted to elucidate the impact of O-GlcNAcylation on CD36 function. ResultsO-GlcNAcylation and CD36 expression were significantly increased in patients with NASH, mouse models of NASH, and palmitic acid-stimulated hepatocytes. Mechanistically, the increase in O-GlcNAcylation facilitated the transcription of CD36 via the NF-κB signalling pathway and stabilized the CD36 protein by inhibiting its ubiquitination, thereby promoting CD36 expression. On the other hand, O-GlcNAcylation facilitated the membrane localization of CD36, fatty acid uptake, and lipid accumulation. However, site-directed mutagenesis of residues S468 and T470 of CD36 reversed these effects. Furthermore, compared with their WT-CD36 counterparts, HFHC-fed S468A&T470A-CD36 mice exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis. Pharmacological inhibition of O-GlcNAcylation and CD36 also mitigated the progression of NASH. ConclusionsO-GlcNAcylation promotes the progression of NAFLD by upregulating CD36 expression and function. Inhibition of CD36 O-GlcNAcylation protects against NASH, highlighting a potentially effective therapeutic approach for individuals with NASH.

The efficacy of multi-disciplinary lifestyle modifications in Taiwanese nonalcoholic steatohepatitis patients.

Lifestyle modification is the standard of care for nonalcoholic fatty liver disease (NAFLD) patients. We aimed to investigate the efficacy of a short-term lifestyle modification program in the disease course of Taiwanese nonalcoholic steatohepatitis (NASH) patients with paired biopsies. All patients received a 6-month, strict multidisciplinary program of lifestyle modifications led by physicians, dieticians, and nursing staff. The histopathological and clinical features were assessed. The endpoints were normalization of transaminase levels, metabolic parameters, a decrease in the NAFLD activity score (NAS) ≥1, and a decrease in the fibrosis stage ≥1. We also aimed to elucidate the predictors associated with disease progression. A total of 37 patients with biopsy-proven NASH were enrolled. The normalization of transaminase levels increased from 0% to 13.5%. There were also significantly increased proportions of patients with normal total cholesterol, triglyceride, and hemoglobin A1c levels. Fifteen (40.5%) patients had an increased NAS ≥1, whereas 10 (27.0%) patients had NAS regression. Twelve (32.4%) patients had increased fibrosis ≥1 stage. Only 2 (5.4%) patients experienced fibrosis regression. A high fasting plasma glucose (FPG) level was associated with NAS progression. Older age and higher transaminase and FPG levels were factors associated with fibrosis progression. Seven (18.9%) patients achieved a body weight reduction >3%, and 4 (57.1%) of them experienced NAS regression. No significant effect of weight reduction on the progression of fibrosis was observed. The short-term lifestyle modification program significantly decreased liver enzymes and metabolic parameters in NASH patients. A more precise or intensive program may be needed for fibrosis improvement.

LincRNA00907 promotes NASH progression by targeting miRNA-942-5p/TAOK1.

The study aims to examine the involvement of lincRNA00907 in the advancement of non-alcoholic steatohepatitis (NASH). The examination was conducted to assess the expression of linc00907 in liver tissues from NASH patients and healthy individuals. High-fat diets induced NASH in mouse models, while palmitic acid/oleic acid treatment was used to create in vitro cell models. Various techniques, such as qRT-PCR, Oil Red O staining and gene knockdown/overexpression, were used to assess the impact of linc00907 on genes related to lipid metabolism and immunity, as well as intracellular lipid accumulation. Furthermore, dual-luciferase reporter assays were carried out to confirm the connection between miRNA-942-5p and linc00907 or TAOK1 mRNA. Linc00907 was found to be significantly upregulated in both NASH patients and NASH mouse models. Overexpression of linc00907 led to an increase in intracellular lipid accumulation, while knockdown of linc00907 resulted in decreased lipid content. It was found that miRNA-942-5p binds with linc00907, and their interaction was confirmed in dual-luciferase reporter assays. Additionally, TAOK1 was predicted to be a downstream target of miRNA-942-5p, and the upregulation of TAOK1 due to linc00907 was reversed by miRNA-942-5p overexpression. linc00907 overexpression reduces apoptosis but can be reversed by TAOK1 knockdown. The reduction of TAOK1 counteracted the impact of linc00907 on gene expression associated with lipid metabolism and immunity, as well as on the accumulation of intracellular lipids. Our research suggests that linc00907 functions as a competitive endogenous RNA (ceRNA) by sequestering miRNA-942-5p, thus increasing the expression of TAOK1 and encouraging lipid accumulation in hepatocytes, leading to the aggravation of NASH development. Targeting the linc00907/miRNA-942-5p/TAOK1 axis may hold therapeutic potential for the treatment of NASH.

From gut to liver: unveiling the differences of intestinal microbiota in NAFL and NASH patients.

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized for its global prevalence and potential progression to more severe liver diseases such as non-alcoholic steatohepatitis (NASH). The gut microbiota plays a pivotal role in the pathogenesis of NAFLD, yet the detailed characteristics and ecological alterations of gut microbial communities during the progression from non-alcoholic fatty liver (NAFL) to NASH remain poorly understood. Methods: In this study, we conducted a comparative analysis of gut microbiota composition in individuals with NAFL and NASH to elucidate differences and characteristics. We utilized 16S rRNA sequencing to compare the intestinal gut microbiota among a healthy control group (65 cases), NAFL group (64 cases), and NASH group (53 cases). Random forest machine learning and database validation methods were employed to analyze the data. Results: Our findings indicate a significant decrease in the diversity of intestinal flora during the progression of NAFLD (p < 0.05). At the phylum level, high abundances of Bacteroidetes and Fusobacteria were observed in both NAFL and NASH patients, whereas Firmicutes were less abundant. At the genus level, a significant decrease in Prevotella expression was seen in the NAFL group (AUC 0.738), whereas an increase in the combination of Megamonas and Fusobacterium was noted in the NASH group (AUC 0.769). Furthermore, KEGG pathway analysis highlighted significant disturbances in various types of glucose metabolism pathways in the NASH group compared to the NAFL group, as well as notably compromised flavonoid and flavonol biosynthesis functions. The study uncovers distinct microbiota characteristics and microecological changes within the gut during the transition from NAFL to NASH, providing insights that could facilitate the discovery of novel biomarkers and therapeutic targets for NAFLD.

Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2

Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.

Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis

Background & aimsUnrestricted endoplasmic reticulum (ER) stress and the continuous activation of ER associated protein degradation (ERAD) pathway might lead to the aggravation of non-alcoholic steatohepatitis (NASH). Derlin-1 has been considered to be an integral part of the ERAD pathway, which is involved in the regulation of the transport and excretion of protein degradation products within ER. However, the regulatory role and mechanism of Derlin-1 in NASH remains unclear. MethodsThe expression of Derlin-1 was firstly detected in the liver of normal and NASH animal model and patient. Then, western diet (WD)-induced NASH mice were administrated with the lentivirus-mediated Derlin-1 knockdown or overexpression. Finally, RIPK3 knockout mice were used to explore the mechanism. The liver injury, hepatic steatosis, inflammation, and fibrosis as well as ER stress signal pathway were evaluated. ResultsThe levels of Derlin-1 were significantly elevated in the liver of WD-fed mice and NASH patients when compared to the control group. Furthermore, Derlin-1 knockdown attenuated WD-induced liver injury, lipid accumulation, inflammatory response, and fibrosis. Conversely, overexpression of Derlin-1 presented the completely opposite results. Mechanistically, Derlin-1 enhanced ER stress pathways and led to necroptosis, and RIPK3 knockout dramatically reduced Derlin-1 expression and reversed the progression of NASH aggravated by Derlin-1. ConclusionsNotably, Derlin-1 is a critical modulator in NASH. It may accelerate the progression of NASH by regulating the activation of the ERAD pathway and further aggravating the ER stress, which might be involved in RIPK3-mediated necroptosis. Therefore, targeting Derlin-1 as a novel intervention point holds the potential to delay or even reverse NASH.

Molecular pathological approach to cancer epigenomics and its clinical application.

Careful microscopic observation of histopathological specimens, accumulation of large numbers of high-quality tissue specimens, and analysis of molecular pathology in relation to morphological features are considered to yield realistic data on the nature of multistage carcinogenesis. Since the morphological hallmark of cancer is disruption of the normal histological structure maintained through cell-cell adhesiveness and cellular polarity, attempts have been made to investigate abnormalities of the cadherin-catenin cell adhesion system in human cancer cells. It has been shown that the CDH1 tumor suppressor gene encoding E-cadherin is silenced by DNA methylation, suggesting that a "double hit" involving DNA methylation and loss of heterozygosity leads to carcinogenesis. Therefore, in the 1990s, we focused on epigenomic mechanisms, which until then had not received much attention. In chronic hepatitis and liver cirrhosis associated with hepatitis virus infection, DNA methylation abnormalities were found to occur frequently, being one of the earliest indications that such abnormalities are present even in precancerous tissue. Aberrant expression and splicing of DNA methyltransferases, such as DNMT1 and DNMT3B, was found to underlie the mechanism of DNA methylation alterations in various organs. The CpG island methylator phenotype in renal cell carcinomawas identified for the first time, and its therapeutic targets were identified by multilayer omics analysis. Furthermore, the DNA methylation profile of nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinomawas clarified in groundbreaking studies. Since then, we have developed diagnostic markers for carcinogenesis risk in NASH patients and noninvasive diagnostic markers for upper urinary tract cancer, as well as developing a new high-performance liquid chromatography-based diagnostic system for DNA methylation diagnosis. Research on the cancer epigenome has revealed that DNA methylation alterations occur from the precancerous stage as a result of exposure to carcinogenic factors such as inflammation, smoking, and viral infections, and continuously contribute to multistage carcinogenesis through aberrant expression of cancer-related genes and genomic instability. DNA methylation alterations at the precancerous stages are inherited by or strengthened in cancers themselves and determine the clinicopathological aggressiveness of cancers as well as patient outcome. DNA methylation alterations have applications as biomarkers, and are expected to contribute to diagnosis, as well as preventive and preemptive medicine.

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathological and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multi-factorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multi-factorial pharmacokinetic interactions. Significance Statement Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multi-factorial pharmacokinetic interaction was observed between silymarin and NAFLD.

Single-cell transcriptome reveals a novel mechanism of C-Kit+-liver sinusoidal endothelial cells in NASH

AimTo understand how liver sinusoidal endothelial cells (LSECs) respond to nonalcoholic steatohepatitis (NASH).MethodsWe profiled single-LSEC from livers of control and MCD-fed mice. The functions of C-Kit+-LSECs were determined using coculture and bone marrow transplantation (BMT) methods.ResultsThree special clusters of single-LSEC were differentiated. C-Kit+-LSECs of cluster 0, Msr1+-LSECs of cluster 1 and Bmp4+Selp+-VECs of cluster 2 were revealed, and these cells with diverse ectopic expressions of genes participated in regulation of endothelial, fibrosis and lipid metabolism in NASH. The number of C-Kit+-primary LSECs isolated from MCD mice was lower than control mice. Immunofluorescence co-staining of CD31 and C-KIT showed C-Kit+-LSECs located in hepatic sinusoid were also reduced in NASH patients and MCD mice, compared to AIH patients and control mice respectively. Interestingly, lipotoxic hepatocytes/HSCs cocultured with C-Kit+-LSECs or the livers of MCD mice receipting of C-Kit+-BMCs (bone marrow cells) showed less steatosis, inflammation and fibrosis, higher expression of prolipolytic FXR and PPAR-α, lower expression of TNF-α and α-SMA. Furthermore, coculturing or BMT of C-Kit+-endothelial derived cells could increase the levels of hepatic mitochondrial LC3B, decrease the degree of mitochondrial damage and ROS production through activating Pink1-mediated mitophagy pathway in NASH.ConclusionsHence, a novel transcriptomic view of LSECs was revealed to have heterogeneity and complexity in NASH. Importantly, a cluster of C-Kit+-LSECs was confirmed to recovery Pink1-related mitophagy and NASH progression.

Expression of immune related genes and possible regulatory mechanisms in different stages of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), which includes simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), is a significant contributor to liver disease on a global scale. The change of immunity-related genes (IRGs) expression level leads to different immune infiltrations. However, the expression of IRGs and possible regulatory mechanisms involved in NAFLD remain unclear. The objective of our research is to investigate crucial genes linked to the development of NAFLD and the transition from SS to NASH. Dataset GSE89632, which includes healthy controls, SS patients, and NASH patients, was obtained using the GEO database. To examine the correlation between sets of genes and clinical characteristics, we employed weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Hub genes were extracted using a network of protein-protein interactions (PPI) and three different machine learning algorithms. To validate the findings, another dataset that is publicly accessible and mice that were subjected to a high-fat diet (HFD) or MCD diet were utilized. Furthermore, the ESTIMATE algorithm and ssGSEA were employed to investigate the immune landscape in the normal versus SS group and SS versus NASH group, additionally, the relationship between immune infiltration and the expression of hub genes was also examined. A total of 28 immune related key genes were selected. Most of these genes expressed reverse patterns in the initial and progressive stages of NAFLD. GO and KEGG analyses showed that they were focused on the cytokine related pathways and immune cell activation and chemotaxis. After screening by various algorithms, we obtained two hub genes, including JUN and CCL20. Validation of these findings was confirmed by analyzing gene expression patterns in both the validation dataset and the mouse model. Ultimately, two hub genes were discovered to have a significant correlation with the infiltration of immune cells. We proposed that there were dynamic changes in the expression levels of IRGs in different stages of NAFLD disease, which led to different immune landscapes in SS and NASH. The findings of our research could serve as a guide for the accurate management of various phases of NAFLD.

Yanggan Jiangmei Formula alleviates hepatic inflammation and lipid accumulation in non-alcoholic steatohepatitis by inhibiting the NF-κB/NLRP3 signaling pathway

The role of NF-κB and the NLRP3 inflammasome in the chronic inflammatory microenvironment of non-alcoholic steatohepatitis (NASH) has been posited as crucial. The Yanggan Jiangmei Formula (YGJMF) has shown promise in ameliorating hepatic steatosis in NASH patients, yet its pharmacological mechanisms remain largely unexplored. This study was conducted to investigate the efficacy of YGJMF in NASH and to elucidate its pharmacological underpinnings. To simulate NASH both in vivo and in vitro, high-fat-diet (HFD) rats and HepG2 cells stimulated with free fatty acids (FFAs) were utilized. The severity of liver injury and lipid deposition was assessed using serum indicators, histopathological staining, micro-magnetic resonance imaging (MRI), and the liver-to-muscle signal intensity ratio (SIRL/M). Furthermore, a combination of enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), immunofluorescence, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting analyses was employed to investigate the NF-κB/NLRP3 signaling pathway and associated cytokine levels. The results from liver pathology, MRI assessments, and biochemical tests in rat models demonstrated YGJMF's significant effectiveness in reducing liver damage and lipid accumulation. Additionally, YGJMF markedly reduced hepatocyte inflammation by downregulating inflammatory cytokines in both liver tissue and serum. Furthermore, YGJMF was found to disrupt NF-κB activation, consequently inhibiting the assembly of the NLRP3 inflammasome in both the in vitro and in vivo models. The preliminary findings of this study suggest that YGJMF may alleviate hepatic steatosis and inhibit the NF-κB/NLRP3 signaling pathway, thereby exerting anti-inflammatory effects in NASH.

Disparities in Liver Transplantation for Nonalcoholic Steatohepatitis in Women.

Nonalcoholic steatohepatitis (NASH) is the fastest-growing indication for liver transplantation (LT). Sex disparities among patients with cirrhosis on the LT waitlist are well known. We wanted to understand these disparities further in women with end-stage liver disease patients listed for NASH cirrhosis in a contemporary cohort. We used data from the Scientific Registry of Transplant Recipients to assess sex racial, and ethnic differences in NASH patients listed for LT. Adults transplanted from August 1997 to June 2021 were included. Inferential statistics were used to evaluate differences with univariate and multivariate comparisons, including competitive risk analysis. During the study time period, we evaluated 12 844 LT for NASH cirrhosis. Women were transplanted at a lower rate (46.5% versus 53.5%; P < 0.001) and higher model for end-stage liver disease (MELD) (23.8 versus 22.6; P < 0.001) than men. Non-White women were transplanted at a higher MELD (26.1 versus 23.1; P < 0.001) than White women and non-White male patients (26.1 versus 24.8; P < 0.001). Graft and patient survivals were significantly different (P < 0.001) between non-White women and White women and men (White and non-White). Evaluation of LT candidates in the United States demonstrates women with NASH cirrhosis have a higher MELD than men at LT. Additional disparities exist among non-White women with NASH as they have higher MELD and creatinine at LT compared with White women. After LT, non-White women have worse graft and patient survival compared with men or White women. These data indicate that non-White women with NASH are the most vulnerable on the LT waitlist.

Compare the Combined Diagnostic Accuracy of Transient Elastography and Visual Liver Score in Assessing Non-Alcoholic Fatty Liver Disease (NAFLD) and Compare it with Liver Biopsy in Morbidly Obese Patients Undergoing Bariatric Surgery: An Observational Study.

A liver biopsy is the gold standard for the diagnosis of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Here, we combine preoperative transient elastography (TE) and intraoperative standardized visual liver score (VLS) which is compared with intraoperative liver biopsy for prediction of NAFLD and NASH in patients undergoing bariatric surgery. Evaluate the combined diagnostic accuracy of TE and VLS in assessing NAFLD or NASH and compare it with liver biopsy in patients undergoing bariatric surgery. In a prospective cohort of 70 morbidly obese undergoing bariatric surgery, preoperative TE and intraoperative VLS were calculated. Findings of TE and VLS were compared with histology from intraoperative liver biopsy. Histologically, 44 (62.85%) had NAFLD (≥ S1). Significant steatosis was seen in 20 (28.57%) while significant fibrosis was visible in 18 (25.71%). Area Under the Receiver Operating Characteristics (AUROC) TE for diagnosis of NAFLD was excellent (0.844, p = 0.001). At the optimal cutoff of 8.1, the positive predictive value (PPV) was 92.9%, and diagnostic accuracy was 90.6%. VLS had a sensitivity of 90.9% for NAFLD. The combined sensitivity of TE + VLS was 95.5% for ruling out NAFLD. Fourteen (20%) had NASH. VLS had a diagnostic accuracy of 97% in identifying NASH in comparison to TE. AUROC-VLS was 0.987, p ≤ 0.001, and a sensitivity of 100%. The overall sensitivity of combined TE and VLS was 100% with a negative predictive value (NPV) of 100%. TE when combined with intraoperative VLS is comparable to liver biopsy and can be used for the diagnosis of NAFLD and NASH in patients undergoing bariatric surgery.

The relationship and diagnostic efficacy of N-terminal propeptide type III collagen in pathological changes associated with non-alcoholic steatohepatitis.

This study delves into the role of N-terminal propeptide type III collagen (PIIINP) in the diagnosis and management of liver pathological changes associated with non-alcoholic steatohepatitis (NASH). We collected baseline information, pathological data, and serum PIIINP levels of 168 patients diagnosed with non-alcoholic fatty liver disease (NAFLD) via ultrasound imaging in our hospital. Based on the non-alcoholic fatty liver disease activity score (NAS), patients with different NAFLD patterns were divided into a Definite NASH group and a Not/borderline group. Differences in PIIINP levels and pathological features between the two groups were compared and analyzed. The diagnostic value of PIIINP for NASH was evaluated using the receiver operating characteristic (ROC) curve. Patients with NASH exhibited significantly higher values of homeostatic model assessment for insulin resistance (HOMA-IR), fibrosis biomarker fibrosis-4 (FIB-4), aminotransferase-to-platelet ratio index (APRI), and serum PIIINP levels than those classified as Not/borderline. A marked increase in the serum concentrations of PIIINP was observed with the severity of fatty degeneration, lobular inflammation, and hepatocellular ballooning. The AUC of PIIINP for diagnosing definite NASH was 0.766 (95% CI: 0.694, 0.839), APRI was 0.634 (95% CI: 0.549, 0.718), and FIB-4 was 0.621 (95% CI: 0.534, 0.708). The AUC of PIIINP for diagnosing definite NASH was significantly higher than that of APRI and FIB-4 (all p<0.05). Utilizing the predetermined threshold values for diagnostic parameters, the PIIINP measure demonstrated a sensitivity of 71.6% and a specificity of 73.6% in diagnosing definitive NASH when its value exceeded 7.72 ng/dL. This yielded a Youden index of 0.45. Similarly, when the APRI measure exceeded 0.21, it exhibited a sensitivity of 60.5% and a specificity of 63.2%, resulting in a Youden index of 0.24. Moreover, when the FIB-4 index surpassed 0.26, it showed a sensitivity of 46.9% and a specificity of 79.3%, culminating in a Youden index of 0.26. NASH patients in this study exhibited significantly elevated PIIINP serum levels, which were closely associated with hepatocyte pathological changes. PIIINP demonstrated superior competence in diagnosing NASH than APRI and FIB-4 and thus offers a viable alternative for the clinical diagnosis of NASH.

Exosomal miR-122, miR-128, miR-200, miR-298, and miR-342 as novel diagnostic biomarkers in NAFL/NASH: Impact of LPS/TLR-4/FoxO3 pathway.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder affecting a quarter of the global residents. Progression of NAFL into nonalcoholic steatohepatitis (NASH) may cause cirrhosis, liver cancer, and failure. Gut microbiota imbalance causes microbial components translocation into the circulation, triggering liver inflammation and NASH-related fibrosis. MicroRNAs (miRNAs) regulate gene expression via repressing target genes. Exosomal miRNAs are diagnostic and prognostic biomarkers for NAFL and NASH liver damage. Our work investigated the role of the gut microbiota in NAFLD pathogenesis via the lipopolysaccharide/toll-like receptor 4/Forkhead box protein O3 (LPS/TLR-4/FoxO3) pathway and certain miRNAs as noninvasive biomarkers for NAFL or its development to NASH. miRNAexpression levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 50 NAFL patients, 50 NASH patients, and 50 normal controls. Plasma LPS, TLR-4, adiponectin, peroxisome proliferator-activated receptor γ (PPAR-γ), and FoxO3 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). In NAFL and NASH patients, miR-122, miR-128, FoxO3, TLR-4, LPS, and PPAR-γ were upregulated while miR-200, miR-298, miR-342, and adiponectin were downregulated compared with the normalcontrol. The examined miRNAs might distinguish NAFL and NASH patients from the normal controlusing receiver operating characteristic analysis. Our study is the first to examine these miRNAs in NAFLD. Our findings imply that these are potentially promising biomarkers for noninvasive early NAFL diagnosis and NASH progression. Understanding the LPS/TLR-4/FoxO3 pathway involvement in NAFL/NASH pathogenesis may aid disease management.

Escherichia coli NF73-1 disrupts the gut-vascular barrier and aggravates high-fat diet-induced fatty liver disease via inhibiting Wnt/β-catenin signalling pathway.

Gut-vascular barrier (GVB) dysfunction has been shown to be a prerequisite for nonalcoholic fatty liver disease (NAFLD) development. However, the causes of GVB disruption and the underlying mechanisms are still elusive. Here, we explored whether and how Escherichia coli (E. coli) NF73-1, a pathogenic E. coli strain isolated from nonalcoholic steatohepatitis patients, contributes to NAFLD by modulating the GVB. C57BL/6J mice were fed with high-fat diet (HFD) or normal diet in the presence or absence of E. coli NF73-1 for the indicated time periods. Intestinal barrier function and infiltration of immune cells were evaluated in these mice. Endothelial cells were exposed to E. coli NF73-1 for barrier integrity analysis. HFD-induced GVB disruption preceded the damage of intestinal epithelial barrier (IEB) as well as intestinal and hepatic inflammatory changes and can be reversed by vascular endothelial growth factor A blockade. Antibiotic treatment prevented mice from HFD-induced liver steatosis by restoration of the GVB. Notably, E. coli NF73-1 caused a more conspicuous damage of GVB than that of the IEB and contributed to NAFLD development. Mechanistically, E. coli NF73-1 dismantled the GVB by inhibiting the Wnt/β-catenin signalling pathway. Activation of Wnt/β-catenin improved the GVB and impeded the translocation of E. coli NF73-1 into the liver invitro and invivo. E. coli NF73-1 disrupts GVB and aggravates NAFLD via inhibiting the Wnt/β-catenin signalling pathway. Targeting E. coli NF73-1 or selectively enhancing the GVB may act as potential avenues for the prevention and treatment of NAFLD.

Macrophage RAGE activation is proinflammatory in NASH.

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.