Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV.

MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV.

MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.

In the present narrative review, we have summarized the current evidence on the natural progression of metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis observed through the placebo arm in clinical trials and observational studies. The outcomes scrutinized throughout our review were histology-related changes, non-invasive fibrosis markers, indicators of decompensation, end-stage hepatic complications, and mortality reported during the different clinical trials. Given the short duration of clinical trials, observational studies were included to obtain better insight into the long-term progression and prognosis of MASH cirrhosis. Lastly, new updates about MASH cirrhosis treatments were listed, and the results of these randomized clinical trials were described to enhance our understanding of our current standing in the treatment of MASH cirrhosis.

Whether include high-sensitivity C-reactive protein (Hs-CRP) in diagnostic flow remains debatable during the updated definition to metabolic dysfunction-associated steatotic liver disease (MASLD) despite systemic inflammation contributes to the disease development and progression. We aimed to identify values of hs-CRP compared to other inflammatory markers derived from routine blood tests in MASLD.

This cross-sectional study included consecutive participants (ultrasound-diagnosed MASLD: 1,006, healthy controls: 582), and 175 patients received liver biopsy., with 733 and 310 patients underwent magnetic resonance imaging proton density fat fraction for liver fat content (LFC) quantification and two-dimensional shear-wave elastography liver stiffness measurements (LSM), respectively.

Multiple linear regression analysis revealed a significant positive association between hs-CRP and LFC among overweight/obesity group patients (β 0.19, P = 0.03), and LSM among lean/normal weight group (β 0.30, P < 0.001). For the metabolic dysfunction-associated steatohepatitis (MASH), the hs-CRP and the ratio of monocytes to high-density lipoprotein both performed well in the overweight/obesity group and type 2 diabetes group (Overweight/obesity group, hs-CPR AUC 0.65 and 0.74, P = 0.02), bu no valuable inflammatory indicators were observed in MASH and liver fibrosis.

Hs-CRP levels are associated with LFC in overweight/obese MASLD and liver stiffness in lean MASLD patients, yet the reported AUC values suggest weak predictive ability.

The study protocol was registered at the Chinese Clinical Trial Registry, (ChiCTR-ChiCTR2000034197), approved by the First Affiliated Hospital of Sun Yat-sen University institutional with the regional medical ethics committees (Approval number: [2020] No. 187), and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Written informed consent was obtained from all the patients.

Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious public health problem, posing an increasingly dangerous threat to human health owing to its increasing prevalence and accompanying intra- and extrahepatic adverse outcomes. Rifaximin is considered to have therapeutic potential for MASH; however, its efficacy remains controversial. Our study aimed to observe the ameliorative effects of rifaximin and explore its possible mechanisms at the cellular level. 1. 42 male C57BL/6J mice were divided into 3 groups, the CON group and MCD group were fed with normal feed and MCD feed for 12 weeks respectively, and the MCD + RFX group was treated with rifaximin by gavage for 4 weeks on the basis of MCD feed. Hematoxylin-eosin staining, Sirius red staining and immunohistochemical staining were used to observe the histopathological changes of liver and intestine. Differences in liver transaminases, inflammatory factors, fibrosis indexes and intestinal tight junction proteins were compared among the 3 groups of mice. 2. A MASH cell model was constructed by inducing HepG2 cells with free fatty acids to observe the effects of rifaximin on MASH in vitro. In addition, the effects of rifaximin on TLR4/NF-κB signaling pathway were explored by applying TLR4 agonist LPS and TLR4 inhibitor TAK-242. Hepatic histopathology was significantly improved in MASH mice after rifaximin treatment, and their serum alanine aminotransferase and aspartate aminotransferase levels were (72.72 ± 5.68) U/L and (222.8 ± 11.22) U/L, respectively, which were significantly lower than those in the MCD group [(293.3 ± 10.69) U/L and (414.1 ± 36.29) U/L, P < 0.05], and the levels of inflammatory factors and fibrosis indicators were reduced. Rifaximin ameliorated intestinal barrier injury with increased expression of intestinal tight junction protein ZO-1 in the MCD + RFX group of mice, and the concentration of LPS-binding proteins (4.92 ± 0.55 vs. 15.82 ± 1.71, P < 0.05) was lower than that in the MCD group. In the NASH cell model, rifaximin similarly exerted inhibitory effects on its inflammatory factors and TLR4/NF-κB signaling pathway. Application of TLR4 inhibitors weakened the inhibitory effect of rifaximin on MASH. Our study supports rifaximin as a potential treatment for MASH, with potential mechanisms related to improving intestinal barrier integrity and downregulating the TLR4/NF-κB signaling pathway.

Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis.

Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model.

Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally widespread chronic liver condition that may progress to severe liver diseases, including advanced liver fibrosis. The high-sensitivity C-reactive protein-to-high-density lipoprotein cholesterol (hs-CRP/HDL-C) index may be a potential indicator for MASLD and advanced liver fibrosis, given its relevance to inflammation and plasma lipids. In this study, the hs-CRP/HDL-C index was investigated in relation to prevalent MASLD and advanced liver fibrosis. The study analyzed secondary data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 database. The hs-CRP/HDL-C index was calculated by the quotient of hs-CRP and HDL-C. Multiple logistic regression models, Cochran-Armitage trend tests, smooth curve fitting, threshold effect analyses, and stratified analyses were used to evaluate whether the hs-CRP/HDL-C index associated with MASLD and advanced liver fibrosis. The study cohort comprised 3684 participants, of whom 1268 (34.42%) were diagnosed with MASLD and 156 (12.28%) with advanced liver fibrosis. Logistic analyses adjusted for covariates revealed positive associations of the hs-CRP/HDL-C index with MASLD and advanced liver fibrosis, consistent across all subgroups. Smooth curve fitting and threshold effect analyses revealed nonlinear relationships of hs-CRP/HDL-C index with MASLD and advanced liver fibrosis, with inflection points at 0.8 for MASLD and 1.2 for advanced liver fibrosis. Additionally, significant interactions were observed between MASLD and covariates such as gender, smoking status, chronic kidney disease (CKD), and cancer. Similarly, the hs-CRP/HDL-C index exhibited positive correlations with advanced liver fibrosis across diverse subgroups, with notable interactions related to cancer. MASLD and advanced liver fibrosis were associated with hs-CRP/HDL-C index, indicating its potential utility as a clinical marker for these conditions.

Arsenic in the environment, such as sodium arsenic (NaAsO2), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here, we found that exposure to NaAsO2 had a suppressive effect on the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2) at the protein and gene levels, and overexpression of CISD2 inhibited NaAsO2-induced ferroptosis and NASH. Additionally, administration of NaAsO2 to hepatocytes triggered mitochondrial dysfunction, manifesting as the release of cytochrome c, impairment of the mitochondrial respiratory chain, and reduction in ATP synthesis. However, these adverse effects were alleviated through overexpression of CISD2. Intracellular iron redistribution was induced by overexpression of CISD2 and inhibited NaAsO2-induced ferroptosis. This inhibition was characterized by a reduction in cytoplasmic iron levels and an increase in mitochondrial iron levels. Our study demonstrated that NaAsO2 induced intracellular iron reorganization and mitochondrial dysfunction through CISD2 inhibition, leading to ferroptosis and NASH. This may provide a novel means of treatment of nonalcoholic fatty liver disease triggered by environmental factors.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, coinciding with aging population. However, limited studies have evaluated its incidence and progression to advanced fibrosis in the elderly population. Therefore, our study aimed to investigate the incidence of MASLD and advanced fibrosis in this age group.

We included 878 686 individuals aged ≥60 years from the Korea National Health Insurance Service-Senior cohort. After excluding participants with preexisting MASLD, 329 388 individuals were finally analyzed. Participants were categorized into four groups based on the presence of overweight/obesity and additional risk factors (aRF) included in the cardiometabolic diagnostic criteria of MASLD.

The overall incidence of MASLD was 1.94 per 100 person-years, and the incidence of advanced fibrosis in MASLD patients was 1.78 per 100 person-years. MASLD development was significantly higher in overweight/obese patients (2.65 per 100 person-years) compared to lean patients (1.09 per 100 person-years), and this trend persisted after stratification by the presence of aRF. Similarly, the incidence of advanced fibrosis among MASLD patients was higher in overweight/obese individuals (2.06 per 100 person-years) compared to lean counterparts (0.87 per 100 person-years), irrespective of aRF.

The lower incidence of MASLD in the elderly population compared to the general population underscores the importance of identifying age-specific risk factors. Overweight/obesity emerged as a robust predictor of MASLD development and advanced fibrosis. Additionally, the presence of additional cardiometabolic risk factors further increased the risk of incident MASLD and advanced fibrosis among the elderly.

The aim of this study was to establish a simple, nonalcoholic fatty liver disease (NAFLD) screening model using readily available variables to identify high-risk individuals in Western Xinjiang, China.

A total of 40 033 patients from the National Health Examination were divided into a training group (70%) and a validation group (30%). Univariate regression and least absolute shrinkage and selection operator models optimized feature selection, while a multivariate logistic regression analysis constructed the prediction model. The model's performance was evaluated using the area under the receiver operating characteristic curve, and its clinical utility was assessed through decision curve analysis.

The nomogram assessed NAFLD risk based on factors such as sex, age, diastolic blood pressure, waist circumference, BMI, fasting plasma glucose, alanine aminotransferase, platelet count, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. The area under the receiver operating characteristic curves were 0.829 for men and 0.859 for women in the development group, and 0.817 for men and 0.865 for women in the validation group. The decision curve analysis confirmed the nomogram's clinical usefulness, with consistent findings in the validation set.

A user-friendly nomogram prediction model for NAFLD risk was successfully developed and validated for Western Xinjiang, China.

The utilization of non-invasive techniques for liver fibrosis and steatosis assessment has gained acceptance as a viable substitute for liver biopsy in clinical practice. This study aimed to establish normative data for the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) by age and gender, as well as to explore the relationship between anthropometric measures, clinical status, and biochemical profile according to the 90th percentile cut-off values for CAP/LSM in a U.S. adult population.

In this cross-sectional analysis, 7.522 US adults aged 20-80 years from the National Health and Nutrition Examination Survey (NHANES 2017-2020) were included. CAP and LSM were quantified using the FibroScan® 502-v2 device. A comprehensive range of data was collected, including sociodemographic, anthropometric, biochemical, lifestyle, and clinical conditions. Participants were segmented by sex and age. The median ± standard deviation (SD) for CAP was significantly lower in women (258.27 ± 61.02 dB/m) than in men (273.43 ± 63.56 dB/m), as was the median ± SD for LSM (women: 5.50 ± 4.12 kPa, men: 6.36 ± 5.63 kPa). Although median CAP and LSM values displayed an upward trend with age, statistical significance was not achieved. Notably, higher liver CAP values (above the 90th percentile) correlated with more pronounced clinical and biochemical profile differences compared to lower CAP values (below the 90th percentile) (p < 0.001).

Our study provides age- and sex-stratified standard values for CAP and LSM in a sizeable, nationally representative cohort of adults. The evidence of sex-specific variations in TE test results from our study sets the stage for future research to further corroborate these findings.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disease that has no effective treatment. Our proprietary probiotic mixture, Prohep, has been proven in a previous study to be helpful in reducing hepatocellular carcinoma (HCC) in vivo. However, its prospective benefits on the treatment of other liver diseases such as MASLD, which is one of the major risk factors in the development of HCC, are unclear. To investigate the potential of Prohep in modulating the development and progression of MASLD, we first explored the effect of Prohep supplementation via voluntary intake in a high-fat diet (HFD)-induced MASLD/metabolic dysfunction-associated steatohepatitis (MASH) murine model. Our results indicated that Prohep alleviated HFD-induced liver steatosis and reduced excessive hepatic lipid accumulation and improved the plasma lipid profile when compared with HFD-fed control mice through suppressing hepatic de novo lipogenesis and cholesterol biosynthesis gene expressions. In addition, Prohep was able to modulate the gut microbiome, modify the bile acid (BA) profile, and elevate fecal short-chain fatty acid (SCFA) levels. Next, in a prolonged HFD-feeding MASLD/MASH model, we observed the effectiveness of Prohep in preventing the transition from MASLD to MASH via amelioration in hepatic steatosis, inflammation, and fibrosis. Taken together, Prohep could ameliorate HFD-induced MASLD and control the MASLD-to-MASH progression in mice. Our findings provide distinctive insights into the development of novel microbial therapy for the management of MASLD and MASH.

NAFLD is thought to affect approximately one-fourth of the world's population. Therefore, we evaluated the role of serum complement and immunoglobulins in the NAFLD pathogenesis.

200 participants were used in this study, divided into two groups; Group I: 100 NAFLD patients and Group II: 100 healthy volunteers. The diagnosis of NAFLD is based on non-invasive methods, following the EASL guideline 2022. IgG, IgM, IgA, C3, and C4 assays were performed on all participants.

When the immunological profiles of patients with NAFLD and healthy controls were compared, it was found that the mean IgA in NAFLD patients was (4.20±5.07), whereas the mean IgA in healthy controls was (2.22±1.05) (P=0.000). Additionally, a significant increase in IgG was found in NAFLD patients (17.08±3.87) compared with healthy controls (11.59±3.34), with a P value of (p<0.001). complement C3 and complement C4 levels significantly increased in nonalcoholic fatty liver disease patients (1.28± 0.61 and 0.40 ± 0.19, respectively), compared to healthy controls (0.90 ±0.27 and 0.30 ±0.12, respectively), with a significant P value (p<0.001 for each).

Elevated IgA, IgG, C3 and C4 exist in patients with NAFLD and could be associated with fatty liver development and progression of hepatic fibrosis in patients with NAFLD.

Systemic immune-inflammatory biomarkers including systemic immune inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have been demonstrated to be associated with the risk and severity of various liver diseases. However, studies on their role and clinical significance in metabolic diseases, especially in nonalcoholic fatty liver disease (NAFLD), are limited and results are inconsistent.

10821 adults aged 20 years or older were enrolled in this cross-sectional study, sourced from six cycles of the National Health and Nutrition Examination Survey (NHANES). Survey-weighted logistic regression was employed to investigate the correlation between systemic immune-inflammatory biomarkers (SII, NLR, PLR, and LMR) and NAFLD risk. Restricted cubic spline regression models and segmented regression models were used to describe nonlinear relationships and threshold effects. Subgroup and sensitivity analyses were also conducted.

After adjusting for all confounding variables, there was a significant positive association observed between ln-transformed SII (OR= 1.46, 95% CI: 1.27-1.69, P <0.001), NLR (OR= 1.25, 95% CI: 1.05-1.49, P =0.015), LMR (OR= 1.39, 95% CI: 1.14-1.69, P = 0.002) with NAFLD. A nonlinear dose-response relationship with an inverted "U"-shaped threshold of 4.64 was observed between ln(PLR) and NAFLD risk. When ln(PLR) was below 4.64, each unit increase in ln(PLR) was associated with a 0.55-fold increase in the risk of NAFLD (OR= 1.55, 95% CI: 1.05-2.31, P <0.05). Conversely, when ln(PLR) exceeded 4.64, each unit increase in ln(PLR) was associated with a 0.40-fold decrease in the risk of NAFLD (OR= 0.60, 95% CI. 0.44-0.81, P <0.05).

ln-transformed SII, NLR, and LMR were linearly associated with NAFLD risk. ln(PLR) showed an inverted "U"-shaped nonlinear dose-response relationship with the risk of NAFLD.

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular-kidney-metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

Lipophagy is a selective degradation of lipids by a lysosomal-mediated pathway, and dysregulation of lipophagy is linked with the pathological hallmark of many liver diseases. Downregulation of lipophagy in liver cells results in abnormal accumulation of LDs (Lipid droplets) in hepatocytes which is a characteristic feature of several liver pathologies such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Contrarily, upregulation of lipophagy in activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and cirrhosis. Lipid metabolism reprogramming in violent cancer cells contributes to the progression of liver cancer. In this review, we have summarized the recent studies focusing on various components of the lipophagic machinery that can be modulated for their potential role as therapeutic agents against a wide range of liver diseases.

The presence of significant liver fibrosis associated with non-alcoholic steatohepatitis (NASH) is regarded as the major prognostic factor in non-alcoholic fatty liver disease (NAFLD). Identification of patients at risk for NASH with significant fibrosis is therefore important. Although the established fibrosis score FIB-4 is suitable to exclude advanced fibrosis, it does not allow the prediction of significant fibrosis in NAFLD patients. We therefore evaluated whether the hepatokine fibroblast growth factor 21 (FGF21), a regulator of glucose and lipid metabolism, might identify 'at-risk NASH' in NAFLD.

FGF21 levels were assessed by enzyme-linked immunosorbent assay in sera from an exploration (n = 137) and a validation (n = 88) cohort of biopsy-proven NAFLD patients with different disease activity and fibrosis stages. In addition, we evaluated whether the use of FGF21 could improve risk stratification in NAFLD patients with low (<1.3) or intermediate (1.3-2.67) FIB-4.

FGF21 levels could significantly discriminate between NASH and non-alcoholic fatty liver (NAFL) patients, even in the absence of diabetes. Moreover, patients with NASH and fibrosis ≥F2 showed significantly higher FGF21 levels compared to NAFLD patients without significant fibrosis. Significantly elevated FGF21 levels could even be detected in NAFLD patients with NASH and significant fibrosis despite low or intermediate FIB-4.

Serological FGF21 detection might allow the identification of NAFLD patients at risk and improves patient stratification in combination with FIB-4.

Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.

To explore the association between levels of remnant cholesterol (RC) and the incidence of non-alcoholic fatty liver disease (NAFLD) in the general population, ultimately leading to the assessment of a novel proposed model combining RC and waist circumference (R-W) as a predictor of NAFLD incidence.

A cross-sectional analysis was conducted of 4913 subjects undergoing physical examinations at Hebei General Hospital, with ultrasound findings being used to classify patients into individuals with and without NAFLD. Median RC values were used to separate subjects into those with low and high levels of RC, after which the predictive performance of RC and the novel R-W model when used to assess NAFLD risk was assessed through multifactorial logistic regression analyses and receiver operating characteristic curves.

Subjects exhibiting higher RC levels were found to exhibit an elevated risk of NAFLD incidence with or without adjusting for confounding factors. The binary logistic regression analysis-based R-W model may thus offer utility as a tool to gauge the risk of NAFLD in the general population, as it outperformed RC or WC alone, particularly when assessing women or individuals < 45 years of age. The area under the ROC curve for this combined R-W model was 0.813 (0.802, 0.824), with respective sensitivity and specificity values of 83.86% and 63.91%, all of which were significantly higher than corresponding values for RC and WC (P < 0.001).

The present supports a strong association between RC levels and NAFLD in the general populace, and the combined R-W model exhibits greater utility as a tool to predict NAFLD incidence relative to RC or WC in isolation, particularly for individuals who are female or <45 years old.

Many liver diseases are driven by inflammation, but imaging to non-invasively diagnose and quantify liver inflammation has been underdeveloped. The inflammatory liver microenvironment is aberrantly oxidising owing in part to reactive oxygen species generated by myeloid leucocytes. We hypothesised that magnetic resonance imaging using the oxidatively activated probe Fe-PyC3A will provide a non-invasive biomarker of liver inflammation.

A mouse model of drug-induced liver injury was generated through intraperitoneal injection of a hepatoxic dose of acetaminophen. A mouse model of steatohepatitis was generated via a choline-deficient, l-amino acid defined high-fat diet (CDAHFD). Images were acquired dynamically before and after intravenous injection of Fe-PyC3A. The contrast agent gadoterate meglumine was used as a non-oxidatively activated negative control probe in mice fed CDAHFD. The (post-pre) Fe-PyC3A injection change in liver vs. muscle contrast-to-noise ratio (ΔCNR) recorded 2 min post-injection was correlated with liver function test values, histologic scoring assigned using the NASH Clinical Research Network criteria, and intrahepatic myeloid leucocyte composition determined by flow cytometry.

For mice receiving i.p. injections of acetaminophen, intrahepatic neutrophil composition correlated poorly with liver test values but positively and significantly with ΔCNR (r = 0.64, p <0.0001). For mice fed CDAHFD, ΔCNR generated by Fe-PyC3A in the left lobe was significantly greater in mice meeting histologic criteria strongly associated with a diagnosis NASH compared to mice where histology was consistent with likely non-NASH (p = 0.0001), whereas no differential effect was observed using gadoterate meglumine. In mice fed CDAHFD, ΔCNR did not correlate strongly with fractional composition of any specific myeloid cell subpopulation as determined by flow cytometry.

Magnetic resonance imaging using Fe-PyC3A merits further evaluation as a non-invasive biomarker for liver inflammation.

Non-invasive tests to diagnose and measure liver inflammation are underdeveloped. Inflammatory cells such as neutrophils release reactive oxygen species which creates an inflammatory liver microenvironment that can drive chemical oxidation. We recently invented a new class of magnetic resonance imaging probe that is made visible to the scanner only after chemical oxidation. Here, we demonstrate how this imaging technology could be applied as a non-invasive biomarker for liver inflammation.

Chronic liver injury and inflammation triggered by metabolic abnormalities initiate the activation of hepatic stellate cells (HSCs), driving fibrosis and parenchymal dysfunction, culminating in disorders such as nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs capable of effectively treating NASH due to the challenges in addressing fibrosis and restoring extracellular matrix (ECM) homeostasis. We discovered a significant up-regulation of interleukin-11 (IL-11) in fibrotic livers using two well-established murine models of NASH. To leverage this signaling pathway, we developed a nanoparticle (NP)-assisted RNA interfering approach that specifically targets activated HSCs (aHSCs), blocking IL-11/ERK signaling to regulate HSC transdifferentiation along with fibrotic remodeling. The most potent NP, designated NP-AEAA, showed enhanced accumulation in fibrotic livers with NASH and was primarily enriched in aHSCs. We further investigated the therapeutic efficacy of aHSC-targeting NP-AEAA encapsulating small interfering RNA (siRNA) against IL11 or its cognate receptor IL11ra1 (termed siIL11@NP-AEAA or siIL11ra1@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both siIL11@NP-AEAA and siIL11ra1@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, siIL11ra1@NP-AEAA exhibits a superior therapeutic effect over siIL11@NP-AEAA, in terms of reducing liver steatosis and fibrosis as well as recovering liver function. These results constitute a targeted nanoparticulate siRNA therapeutic approach against the IL-11 signaling pathway of aHSCs in the fibrotic liver, offering a promising therapeutic intervention for NASH and other diseases.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome with a rapidly increasing prevalence globally. Plantamajoside (PMS), a phenylethanoid glycoside component extracted from Plantago asiatica, has various biological properties. However, its effect on NAFLD remains unknown. The study aimed to explore the effect and mechanism of PMS on NAFLD in the high-fat diet (HFD)-feeding rats. PMS induced a decrease in body and liver weight, and the amelioration in the blood lipid parameters and pathological symptoms in HFD-feeding rats. The increase in the serum concentrations and the relative protein expressions of proinflammatory factors was decreased by the PMS treatment in HFD-induced NAFLD rats. Additionally, PMS reduced the excessive lipid vacuoles, and modified the relative expressions of proteins involved in the fatty acid synthesis and uptake in HFD-feeding rats. Mechanically, the downregulation of AMPK/Nrf2 pathway in HFD-feeding rats was restored by the PMS treatment. Inhibition of AMPK pathway reversed the PMS-induced the increase in the level of inflammatory factors, pathological symptoms, excessive lipid vacuoles, and the relative expression of proteins involved in the fatty acid synthesis and uptake. Collectively, PMS ameliorated immune dysregulation and abnormal hepatic lipid metabolism by activating AMPK/Nrf2 pathway in rats with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as "two-hit hypothesis", advancing with a "third hit" of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/β-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/β-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.

There are emerging studies suggesting that non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disease with multiple etiologies and molecular phenotypes. Fibrosis is the key process in NAFLD progression. In this study, we aimed to explore molecular phenotypes of NAFLD with a particular focus on the fibrosis phenotype and also aimed to explore the changes of macrophage subsets in the fibrosis subset of NAFLD.

To assess the transcriptomic alterations of key factors in NAFLD and fibrosis progression, we included 14 different transcriptomic datasets of liver tissues. In addition, two single-cell RNA sequencing (scRNA-seq) datasets were included to construct transcriptomic signatures that could represent specific cells. To explore the molecular subsets of fibrosis in NAFLD based on the transcriptomic features, we used a high-quality RNA-sequencing (RNA-seq) dataset of liver tissues from patients with NAFLD. Non-negative matrix factorization (NMF) was used to analyze the molecular subsets of NAFLD based on the gene set variation analysis (GSVA) enrichment scores of key molecule features in liver tissues.

The key transcriptomic signatures on NAFLD including non-alcoholic steatohepatitis (NASH) signature, fibrosis signature, non-alcoholic fatty liver (NAFL) signature, liver aging signature and TGF-β signature were constructed by liver transcriptome datasets. We analyzed two liver scRNA-seq datasets and constructed cell type-specific transcriptomic signatures based on the genes that were highly expressed in each cell subset. We analyzed the molecular subsets of NAFLD by NMF and categorized four main subsets of NAFLD. Cluster 4 subset is mainly characterized by liver fibrosis. Patients with Cluster 4 subset have more advanced liver fibrosis than patients with other subsets, or may have a high risk of liver fibrosis progression. Furthermore, we identified two key monocyte-macrophage subsets which were both significantly correlated with the progression of liver fibrosis in NAFLD patients.

Our study revealed the molecular subtypes of NAFLD by integrating key information from transcriptomic expression profiling and liver microenvironment, and identified a novel and distinct fibrosis subset of NAFLD. The fibrosis subset is significantly correlated with the profibrotic macrophages and M2 macrophage subset. These two liver macrophage subsets may be important players in the progression of liver fibrosis of NAFLD patients.

We conducted a meta-analysis to summarize the rates of progression to and regression of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and fibrosis in adults with nonalcoholic fatty liver disease (NAFLD).

We searched PubMed/Medline and 4 other databases from 1985 through 2020. We included observational studies and randomized controlled trials in any language that used liver biopsy or imaging to diagnose NAFLD in adults with a follow-up period ≥48 weeks. Rates were calculated as incident cases per 100 person-years and pooled using the random-effects Poisson distribution model. Heterogeneity was assessed using the I2 statistic.

We screened 9744 articles and included 54 studies involving 26,738 patients. Among observational studies, 20% of healthy adults developed NAFL (incidence rate, 4.8/100 person-years) while 21% of people with fatty liver had resolution of NAFL (incidence rate, 2.4/100 person-years) after a median of approximately 4.5 years. In addition, 31% of patients developed NASH after 4.7 years (incidence rate, 7.4/100 person-years), whereas in 29% of those with NASH, resolution occurred after a median of 3.5 years (incidence rate, 5.1/100 person-years). Time to progress by 1 fibrosis stage was 9.9, 10.3, 13.3, and 22.2 years for F0, F1, F2, and F3, respectively. Time to regress by 1 stage was 21.3, 12.5, 20.4, and 40.0 years for F4, F3, F2, and F1, respectively. Rates estimated from randomized controlled trials were higher than those from observational studies.

In our meta-analysis, progression to NASH was more common than regression from NASH. Rates of fibrosis progression were similar across baseline stage, but patients with advanced fibrosis were more likely to regress than those with mild fibrosis.

As a result of the obesity epidemic, Nonalcoholic fatty liver disease (NAFLD) and its complications have increased among millions of people. Consequently, a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis; metabolic-associated fatty liver disease (MAFLD). This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD. This article discusses the rationale behind the nomenclature change, the main differences, and its clinical implications.

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Non-resolving inflammation, triggered by sustained accumulation of lipids, is an important driving force of NASH. Thus, unveiling metabolic immune regulation could help better understand the pathology and intervention of NASH. In this study, we found the recruitment of neutrophils is an early inflammatory event in NASH mice, following the formation of neutrophil extracellular traps (NETs). NET is an initiating factor which exacerbates inflammatory responses in macrophages. Inhibition of NETs using DNase I significantly alleviated inflammation in NASH mice. We further carried out a metabolomic study to identify possible metabolic triggers of NETs, and linoleic acid (LA) metabolic pathway was the most altered pathway. We re-analyzed published clinical data and validated that LA metabolism was highly correlated with NASH. Consistently, both LA and γ-linolenic acid (GLA) were active in triggering NETs formation by oxidative burst. Furthermore, we identified silybin, a hepatoprotective agent, as a potent NETosis inhibitor, which effectively blocked NETs formation both in vitro and in vivo. Together, this study not only provide new insights into metabolism-immune causal link in NASH progression, but also demonstrate silybin as an important inhibitor of NETs and its therapeutical potential in treating NETosis-related diseases.

Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. Pemafibrate was reported to reduce ALT in non-alcoholic fatty liver disease (NAFLD) patients, but efficacy was not clearly elucidated due to the small size of previous study populations. Therefore, we explored pemafibrate efficacy in NAFLD patients.

We retrospectively evaluated pemafibrate efficacy on liver enzymes (n = 132) and liver shear wave velocity (SWV, n = 51) in NAFLD patients who had taken pemafibrate for at least 24 weeks.

Patient ALT levels were decreased from 81.0 IU/L at baseline to 48.0 IU/L at week 24 (P < 0.0001). Serum levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and triglyceride (TG) were significantly decreased, and high-density lipoprotein cholesterol and platelet count were significantly increased, with no change in body weight being observed. Study participant SWV values decreased from 1.45 m/s at baseline to 1.32 m/s at week 48 (P < 0.001). Older age (P = 0.035) and serum TG levels (P = 0.048) were significantly associated with normalized ALT. Changes in AST, ALT, γ-GTP and body weight were significantly correlated with change in SWV.

Pemafibrate significantly improves liver function, serum TG and liver stiffness in NAFLD patients. Pemafibrate is a promising therapeutic agent for NAFLD and may be a candidate for NAFLD patients with elevated TG.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that affects approximately one-quarter of the global adult population, posing a significant threat to human health with wide-ranging social and economic implications. The main characteristic of NAFLD is considered that the excessive fat is accumulated and deposited in hepatocytes without excess alcohol intake or some other pathological causes. NAFLD is a progressive disease, ranging from steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Therefore, NAFLD will probably emerge as the leading cause of end-stage liver disease in the coming decades. Unlike other highly prevalent diseases, NAFLD has received little attention from the global public health community. Liver biopsy is currently considered the gold standard for the diagnosis and staging of NAFLD because of the absence of noninvasive and specific biomarkers. Due to the complex pathophysiological mechanisms of NAFLD and the heterogeneity of the disease phenotype, no specific pharmacological therapies have been approved for NAFLD at present, although several drugs are in advanced stages of development. This review summarizes the current evidence on the pathogenesis, diagnosis and treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, with a global prevalence of approximately 30%. However, the prevalence of NAFLD has been variously reported depending on the comorbidities. The rising prevalence of obesity in both the adult and pediatric populations is projected to consequently continue increasing NAFLD prevalence. It is a major cause of chronic liver disease worldwide, including cirrhosis and hepatocellular carcinoma (HCC). NAFLD has a variety of clinical phenotypes and heterogeneity due to the complexity of pathogenesis and clinical conditions of its occurrence, resulting in various clinical prognoses. In this article, we briefly described the basic definition of NAFLD and classified the subtypes based on current knowledge in this field.

It had been evident that non-alcoholic fatty liver disease (NAFLD) is the new era epidemic. Despite emergence of many drugs on the pipeline that considered candidates to cure NAFLD/NASH, the critical need for defining the cohort liable to fibrosis progression is yet unmet.

Evaluate ABCA1 (rs1800977) genotyping as a noninvasive predictor of liver fibrosis severity.

This study included 118 liver biopsy-proven NAFLD-patients. According to Metavir-fibrosis-staging, cases were divided to early fibrosis (74 cases), and 44 cases with significant fibrosis (>F2), added to 49 healthy control subjects. All patients were subjected to liver function tests, lipids profile, triglyceride TG index, and hepatic steatosis index (HSI) and real-time PCR ABCA1 SNP (rs1800977).

Significant differences in transaminases (p > .05), albumin (p < .009), cholesterol (p0.03), low density lipoproteins (LDL) (0.006), triglycerides (p < .001), HSI (p < .001), FIB4 (p < .001) and APRI (p < .001) were reported in those with significant than early fibrosis and control groups. CC was the most prevalent in significant (36.4%) than early fibrosis (13.5%) and control groups (8.2%), with prevalence of C allele in significant fibrosis (p ≤ .003). Univariate analysis revealed that DM (p ≤ .001), TG index (p ≤ .022), cholesterol (p ≤ .03), HSI (p ≤ .006), LDL (p ≤ .02), HDL (p ≤ .01), APRI (p ≤ .02) and CC genotype (p ≤ .005) were the main factors affecting fibrosis progression in NAFLD. However multivariate analysis proved only the role of HSI (p ≤ .005), LDL (p ≤ .02), HDL (p ≤ .003) and CC genotype (p ≤ .03) in predicting fibrosis severity.

Dyslipidemias, hepatic steatosis index and ABCA1 (rs1800977) gene polymorphism CC genotype; were the only independent predictors of advanced fibrosis in NAFLD-patients.

The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.

Early detection and grading of liver inflammation are important for the management of nonalcoholic fatty liver disease (NAFLD) patients. There is still lack of a noninvasive way for the inflammation characterization in NAFLD.

To assess liver inflammation grades by water specific T1 (wT1) in a rat model.

Prospective.

A total of 65 male rats with methionine-choline-deficient diet-induced NAFLD and 15 male normal rats as control.

A 3 T; multiecho variable flip angle gradient echo sequence.

The wT1 and proton density fat fraction were quantified. Inflammation and fibrosis were assessed histologically with H&E and Sirius red stained slices according to the nonalcoholic steatohepatitis scoring system. Inflammation grade was scored with G0/G1/G2/G3 as none/mild/moderate/severe inflammation in NALFD rats. G0 + G1 and G2 + G3 were combined as none-to-mild grade (GL) and moderate-to-severe grade (GH) inflammation groups.

Analysis of variance (ANOVA), Mann-Whitney U test, Spearman's correlation, and receiver operating characteristic (ROC) analysis were performed. The areas under ROC (AUROC) was used for the diagnostic performance of wT1 in discriminating GH and GL. A P value < 0.01 was considered statistically significant.

Seventy-six rats were included in the analysis. The numbers in G0-G3 groups were 5, 16, 13, and 27. wT1 of G0-G3 was 568.55 ± 63.93 msec, 582.53 ± 62.98 msec, 521.21 ± 67.31 msec, and 508.79 ± 60.53 msec. A moderate but significant negative correlation between wT1 and histopathological inflammation grades was observed (r_s  = -0.42). The wT1 of GH (512.80 ± 62.22 msec) was significantly lower than GL (579.20 ± 61.89 msec). The AUROC of wT1 was 0.79, and the optimal cut-off of wT1 was 562.64 msec (sensitivity: 90%, specificity: 76%), for the discrimination of GL and GH.

wT1 could differentiate none-to-mild inflammation from moderate-to-severe inflammation in the early stage of the NAFLD rat model.

1 TECHNICAL EFFICACY: Stage 1.

Diet and lifestyle are crucial factors that influence the susceptibility of humans to nonalcoholic fatty liver disease (NAFLD). Personalized diet patterns chronically affect the composition and activity of microbiota in the human gut; consequently, nutrition-related dysbiosis exacerbates NAFLD via the gut-liver axis. Recent advances in diagnostic technology for gut microbes and microbiota-derived metabolites have led to advances in the diagnosis, treatment, and prognosis of NAFLD. Microbiota-derived metabolites, including tryptophan, short-chain fatty acid, fat, fructose, or bile acid, regulate the pathophysiology of NAFLD. The microbiota metabolize nutrients, and metabolites are closely related to the development of NAFLD. In this review, we discuss the influence of nutrients, gut microbes, their corresponding metabolites, and metabolism in the pathogenesis of NAFLD.