Nonalcoholic Fatty Liver Disease Research Articles

Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via extracellular vesicles

Background & Aims: Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear. Approach & Results: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet–bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS production, and apoptosis. Conclusions: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.

The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.

Association Between Noninvasive Liver Fibrosis Scores and Heart Failure in a General Population.

The association between nonalcoholic fatty liver disease and cardiovascular disease is firmly established, yet the association between noninvasive liver fibrosis scores and cardiovascular events remains a topic of uncertainty. Our study aimed to explore the association between liver fibrosis and heart failure. The data set was from the National Health and Nutrition Examination Survey 2011 to 2018. Advanced hepatic fibrosis risk was assessed through 3 noninvasive liver fibrosis scores: Fibrosis-4 score (FIB-4), the nonalcoholic fatty liver disease fibrosis score (NFS), and the aspartate aminotransferase to platelet ratio index (APRI). We included 19 695 eligible participants. The national prevalence of advanced liver fibrosis risk in the United States was 4.20%, 8.06%, and 0.35% as determined by FIB-4, NFS, and APRI scores, respectively. Weighted logistic regression analysis revealed significant associations between advanced liver fibrosis risk and the prevalence of heart failure (continuous variables, FIB-4: odds ratio [OR], 1.15 [95% CI, 1.07-1.23]; NFS: OR, 1.42 [95% CI, 1.23-1.64]; APRI: OR, 1.44 [95% CI, 1.15-1.81]). When the scores were assessed as categorical variables, the results were still significant (FIB-4 ≥2.67 versus FIB-4 <1.3: OR, 2.18 [95% CI, 1.47-3.24]; NFS ≥0.675 versus NFS <-1.455: OR, 2.53 [95% CI, 1.37-4.68]). Subgroup analysis found that the association between APRI and heart failure was stronger in female patients. In the general US population, the prevalence of advanced liver fibrosis risk varied between 0.35% and 8.06% as indicated by noninvasive liver fibrosis scores. FIB-4, NFS, and APRI scores were linked to an elevated prevalence of heart failure.

Burden of liver steatosis and liver fibrosis in a large cohort of people living with HIV.

Liver steatosis (LS) and liver fibrosis (LF) can increase the risk of cardiovascular disease in people with HIV, but their prevalence and associated factors are poorly understood. This study aimed to assess the prevalence of and factors associated with LS and LF in a large cohort of people with HIV. We conducted a cross-sectional study of consecutive people with HIV attending the Clinic of Barcelona from September 2022 to September 2023, excluding those with chronic B or/and C hepatitis virus coinfection. LS was assessed using the Hepatic Steatosis Index (HSI) and Fatty Liver Index (FLI), and LF was assessed using the Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS), Fibrosis-4 score (FIB-4), and the European AIDS Clinical Society (EACS) algorithm in both the whole cohort (cohort 1) and in a specific cohort more susceptible to liver disease (cohort 2). We identified independent variables associated with LS and LF using logistic regression. Cohort 1 included 4664 people with HIV; 76% and 37% of them had available HSI and FLI data, LS was present in 28% and 19%, respectively. LF risk was present in 1%, 2%, and 1% of people with HIV according to NFS, FIB-4, and EACS algorithm scores, respectively. Cohort 2 included 1345 people with HIV; 60% and 30% of them had available HSI and FLI data, LS affected 55% and 43% and LF 2%, 5%, or 3%, respectively. Factors associated with LS included current CD4 cell count, diabetes, and hypertension, whereas LF was associated with previous exposure to dideoxynucleoside drugs and current CD4 to LF. Current integrase strand transfer inhibitor (INSTI) therapy appeared protective for LF in cohort 1. In this study, one in four people with HIV had LS, and the prevalence rose to one in two in those with cardiovascular risk factors. The prevalence of LF was low, but it should be considered in older people with HIV with low CD4 counts or high aspartate transaminase levels. A possible protective effect from INSTIs deserves further investigation.

Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population.

Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid-mTOR-FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.

Obesity and risk for liver disease: a two-sample Mendelian randomisation study.

The associations between obesity and liver diseases are complex and diverse. To explore the causal relationships between obesity and liver diseases, we applied two-sample Mendelian randomisation (MR) and multivariable MR analysis. The data of exposures (BMI and WHRadjBMI) and outcomes (liver diseases and liver function biomarker) were obtained from the open genome-wide association study database. A two-sample MR study revealed that the genetically predicted BMI and WHRadjBMI were associated with non-alcoholic fatty liver disease, liver fibrosis and autoimmune hepatitis. Obesity was not associated with primary biliary cholangitis, liver failure, liver cell carcinoma, viral hepatitis and secondary malignant neoplasm of liver. A higher WHRadjBMI was associated with higher levels of biomarkers of lipid accumulation and metabolic disorders. These findings indicated independent causal roles of obesity in non-alcoholic fatty liver disease, liver fibrosis and impaired liver metabolic function rather than in viral or autoimmune liver disease.

Palmitic Acid Induced a Dedifferentiation Profile at the Transcriptome Level: A Collagen Synthesis but no Triglyceride Accumulation in Hepatocyte-Like Cells Derived From Human-Induced Pluripotent Stem Cells Cultivated Inside Organ on a Chip.

Nonalcoholic fatty liver disease (NAFLD) is one of the main causes of critical liver diseases leading to steatosis, steatohepatitis, fibrosis, and ultimately to liver cirrhosis and hepatic carcinoma. In this study, the effect of palmitic acid (PA), one of the most abundant dietary fatty acids, was investigated using an organ-on-a-chip (OoC) technology on hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSCs). After 1 week of hepatic maturation, followed by 1 week of exposure, the transcriptomic analysis showed lower liver transcription factor activity. It also revealed that 318 genes were differentially expressed between the control and 0.5-mM PA conditions. The 0.5-mM PA conditions were characterized by the downregulation of hepatic markers (liver transcription factors, phase I and phase II metabolism genes) of lipidic genes (metabolism and transport). In parallel, the 0.5-mM PA treatment upregulated several extracellular matrix genes (such as collagen genes). The physiopathological staining demonstrated no lipid accumulation in our model and confirmed the secretion of collagen in the 0.5-mM PA conditions. However, the production of albumin, the metabolic biotransformation by the cytochrome P450 enzymes, and the biliary acid concentrations were not altered by the PA treatments. Overall, our data illustrated the response to PA characterized by an early stage of dedifferentiation observed at the transcriptomic levels associated with a modification of the collagenic profile but without lipid accumulation. We believe that our model provides new insight of the onset of palmitic lipotoxicity in the early stage of NAFLD.

Potential diagnostic markers and therapeutic targets for non-alcoholic fatty liver disease and ulcerative colitis based on bioinformatics analysis and machine learning

BackgroundNon-alcoholic fatty liver disease (NAFLD) and ulcerative colitis (UC) are two common health issues that have gained significant global attention. Previous studies have suggested a possible connection between NAFLD and UC, but the underlying pathophysiology remains unclear. This study investigates common genes, underlying pathogenesis mechanisms, identification of diagnostic markers applicable to both conditions, and exploration of potential therapeutic targets shared by NAFLD and UC.MethodsWe obtained datasets for NAFLD and UC from the GEO database. The DEGs in the GSE89632 dataset of the NAFLD and GSE87466 of the UC dataset were analyzed. WGCNA, a powerful tool for identifying modules of highly correlated genes, was employed for both datasets. The DEGs of NAFLD and UC and the modular genes were then intersected to obtain shared genes. Functional enrichment analysis was conducted on these shared genes. Next, we utilize the STRING database to establish a PPI network. To enhance visualization, we employ Cytoscape software. Subsequently, the Cytohubba algorithm within Cytoscape was used to identify central genes. Diagnostic biomarkers were initially screened using LASSO regression and SVM methods. The diagnostic value of ROC curve analysis was assessed to detect diagnostic genes in both training and validation sets for NAFLD and UC. A nomogram was also developed to evaluate diagnostic efficacy. Additionally, we used the CIBERSORT algorithm to explore immune infiltration patterns in both NAFLD and UC samples. Finally, we investigated the correlation between hub gene expression, diagnostic gene expression, and immune infiltration levels.ResultsWe identified 34 shared genes that were found to be associated with both NAFLD and UC. These genes were subjected to enrichment analysis, which revealed significant enrichment in several pathways, including the IL-17 signaling pathway, Rheumatoid arthritis, and Chagas disease. One optimal candidate gene was selected through LASSO regression and SVM: CCL2. The ROC curve confirmed the presence of CCL2 in both the NAFLD and UC training sets and other validation sets. This finding was further validated using a nomogram in the validation set. Additionally, the expression levels of CCL2 for NAFLD and UC showed a significant correlation with immune cell infiltration.ConclusionThis study identified a gene (CCL2) as a biomarker for NAFLD and UC, which may actively participate in the progression of NAFLD and UC. This discovery holds significant implications for understanding the progression of these diseases and potentially developing more effective diagnostic and treatment strategies.

Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

Association of serum klotho with cognitive function among individuals with nonalcoholic fatty liver disease

IntroductionThis study investigated the potential link between serum klotho levels and cognitive function in patients with non-alcoholic fatty liver disease (NAFLD).Materials and MethodsUtilizing NHANES data from 2011 to 2014, the research included 356 eligible participants. NAFLD was identified with the United States Fatty Liver Index (US-FLI), and cognition was measured by various tests including the Animal Fluency Test (AFT), Digit Symbol Substitution Test (DSST), Immediate Recall Test (IRT), and Delayed Recall Test (DRT). Weighted logistic regression and restricted cubic splines were employed to analyze the relationship between klotho levels and cognitive scores.ResultsA significant nonlinear association was observed between klotho levels and the performance in DSST and Delayed Recall Test (DRT). After controlling for confounding factors, the study found a positive association between higher serum klotho levels and improved cognitive performance in both AFT and DSST. However, there was no significant relationship between klotho levels and the IRT or DRT, regardless of whether the natural logarithm or quartile was considered.DiscussionThe findings suggest that a higher serum klotho level may be positively correlated with better cognitive performance in NAFLD patients.

Lack of Efficacy of Pomegranate Supplementation on Insulin Resistance and Sensitivity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The objective of this study is to assess the impact of pomegranate supplements on insulin resistance (IR) and insulin sensitivity through a systematic review and meta-analysis of randomized controlled trials (RCTs). Additionally, we aim to analyze the differences in efficacy among various pomegranate extracts and the sensitivity of different diseases to pomegranate supplementation. We conducted searches in PubMed, Embase, Web of Science, and Cochrane Library up to October 30, 2023, for relevant studies published in English. The treatment group required the intake of pomegranate extract for a minimum of 4 weeks, with no restrictions on the extract type. The control group received a placebo or a treatment excluding pomegranate extract. The primary outcome was homeostatic model assessment for insulin resistance (HOMA-IR) and fasting insulin (FI), and the secondary outcome was quantitative insulin sensitivity check index (QUICKI). RoB 2 was used to assess the risk of bias in the original studies. We pre-specified subgroup analyses based on types of intervention, intervention duration, health condition, and intervention dose. Sensitivity analysis was conducted to validate result stability, utilizing Begg's test and Egger's test for publication bias. Data synthesis and analysis were performed using Stata 15.1 software. This study included a total of 15 RCTs with 673 participants conducted in 7 countries. Risk of bias results indicated an overall low risk of bias of the articles. Participants included healthy individuals, overweight and obese individuals, non-alcoholic fatty liver disease (NAFLD) patients, type 2 diabetes (T2DM) patients, polycystic ovary syndrome (PCOS) patients, metabolic syndrome (MS) patients, and individuals with hyperlipidemia. Pomegranate extract variations included pomegranate juice (PJ), pomegranate seed oil (PSO) capsule, pomegranate/pomegranate peel (PP) extract capsule, and pomegranate peel-added bread. The control groups primarily received placebo treatments with varying dosage and frequency. No adverse reactions were reported in any of the studies. The summary results showed that compared to the control groups, pomegranate extract had no significant impact on improving HOMA-IR levels in participants (WMD = -0.03, 95%CI: -0.37 to 0.31, and p = 0.851) and FI (WMD = -0.03, 95%CI: -0.42 to 0.36, and p = 0.862). Additionally, there was no significant advantage of pomegranate extract on QUICKI changes in T2DM and PCOS patients (WMD = 0.00, 95%CI: 0.00 to 0.01, and p = 0.002). Subgroup analysis results indicated that pomegranate extract could improve HOMA-IR levels in PCOS patients (WMD = -0.42, 95%CI: -0.54 to -0.29, and p < 0.001) and FI levels in T2DM, PCOS, and NAFLD patients. Our results indicate that pomegranate extract only improves HOMA-IR and FI levels in PCOS patients and FI levels in T2DM and NAFLD patients. No significant difference has been found for HOMA-IR, FI, or QUICKI in other metabolic diseases. The current evidence suggests that we should interpret the value of pomegranate extract in regulating IR and sensitivity cautiously. In the future, there is a need for more rigorously designed RCTs to specifically evaluate the impact of pomegranate supplementation on insulin sensitivity in patients with NAFLD, PCOS, and T2DM.

Synergistic impact of Composite Dietary Antioxidant Index and physical activity on fatty liver disease

BackgroundThe relationship between dietary antioxidants and fatty liver disease remains a topic of debate. This study aimed to examine the association between the Composite Dietary Antioxidant Index (CDAI) and nonalcoholic fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD).MethodsThe study analyzed data from the 2003–2018 cycles of the National Health and Nutrition Examination Survey. The study included 16,321 individuals aged 20–85 years. Food and nutrient intake data were based on the 24-h recall method. Multivariate logistic regression models were employed to examine the relationship between CDAI and NAFLD/MAFLD.ResultsIn the fully adjusted multivariate logistic regression model, CDAI demonstrated a significant negative correlation with NAFLD and MAFLD. Mediation analysis showed that inflammatory factors partially mediated the relationship between CDAI and NAFLD/MAFLD prevalence. The combination of high CDAI levels with effective physical activity was associated with a greater reduction in NAFLD/MAFLD prevalence than high CDAI levels alone.ConclusionOur study highlighted a negative association between CDAI and NAFLD/MAFLD, mediated by inflammatory factors. Additionally, participants with characteristics of active physical activity and high levels of CDAI were more strongly correlated with the reduced prevalence of NAFLD/MAFLD. Further research in clinical cohorts should be conducted to comprehensively investigate the impact of CDAI on NAFLD/MAFLD prevalence.

Insights of gut-liver axis in hepatic diseases: Mechanisms, clinical implications, and therapeutic potentials

With the rising prevalence of chronic liver diseases worldwide, there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease. Currently, the most common causes of liver disease are non-alcoholic fatty liver disease, hepatitis, and alcoholic liver disease. Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis. In this review, we analyse the relationship between the gut and liver and their significance in liver disease. This two-way relationship has interesting effects on each other in liver diseases. The gut microbiota, through its metabolites, influences the metabolism in numerous ways. Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases. Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.

Diagnostic and prognostic value of plasma lipocalin-2 levels in patients with metabolic dysfunction–associated steatotic liver disease

Abstract Background Non-Alcoholic Fatty Liver Disease, recently better recognised as Metabolic Dysfunction–Associated Steatotic Liver Disease, is the most prevalent form of chronic liver disease at present time. It is estimated to impact 32% of the world's population, hence representing a significant health burden. Aim of the work To assess the significance of plasma Lipocalin-2 (LCN2) levels in the diagnosis and prognosis of NAFLD patients. Patients and methods In this retrospective case–control study we recruited 102 subjects aged between 18 and 70 years. The included participants were split into two study groups. Group I: 51 NAFLD patients (61% men, 39% females) and Group II: 51 healthy controls (51% men and 49% females), for whom plasma LCN2 levels were assessed and correlated with NAFLD fibrosis score, FIB4 and fatty liver index. Results In this study, LCN2 levels in NAFLD patients were significantly greater compared to individuals in the control group (p &lt; 0.001), with a mean of 1893.214 ± 1002.852 ng/dL in the cases and a mean of 466.020 ± 397.699 ng/dL in the controls. This suggests the use of LCN2 as a possible diagnostic marker of NAFLD. The mean LCN2 levels in this study also significantly increased as the grade of fatty liver increased from I to III (p &lt; 0.001). This in turn proposes the use of LCN2 as a prognostic marker for NAFLD progression. LCN2 also significantly correlated with the fatty liver index and NAFLD Fibrosis scoring systems, but not with Fib-4. With an area under the ROC of 0.906, it demonstrated excellent diagnostic performance with 84% sensitivity, 90% specificity, 89.6% PPV and 85.2% NPV for the prediction of NAFLD patients. Conclusion Lipocalin-2 performs as a diagnostic and a possible prognostic marker for metabolic dysfunction-associated steatotic liver disease.

The Interplay of Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: A Call for Integrated Management.

The Interplay of Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: A Call for Integrated Management.

Multiple Machine Learning Identifies Key Gene PHLDA1 Suppressing NAFLD Progression.

Non-alcoholic fatty liver disease (NAFLD) poses a serious global health threat, with its progression mechanisms not yet fully understood. While several molecular markers for NAFLD have been developed in recent years, a lack of robust evidence hampers their clinical application. Therefore, identifying novel and potent biomarkers would directly aid in the prediction, prevention, and personalized treatment of NAFLD. We downloaded NAFLD-related datasets from the Gene Expression Omnibus (GEO). Differential expression analysis and functional analysis were initially conducted. Subsequently, Weighted Gene Co-expression Network Analysis (WGCNA) and multiple machine learning strategies were employed to screen and identify key genes, and the diagnostic value was assessed using Receiver Operating Characteristic (ROC) analysis. We then explored the relationship between genes and immune cells using transcriptome data and single-cell RNA sequencing (scRNA-seq) data. Finally, we validated our findings in cell and mouse NAFLD models. We obtained 23 overlapping differentially expressed genes (DEGs) across three NAFLD datasets. Enrichment analysis revealed that DEGs were associated with Apoptosis, Parathyroid hormone synthesis, secretion and action, Colorectal cancer, p53 signaling pathway, and Biosynthesis of unsaturated fatty acids. After employing machine learning strategies, we identified one gene, pleckstrin homology like domain family A member 1 (PHLDA1), downregulated in NAFLD and showing high diagnostic accuracy. CIBERSORT analysis revealed significant associations of PHLDA1 with various immune cells. Single-cell data analysis demonstrated downregulation of PHLDA1 in NAFLD, with PHLDA1 exhibiting a significant negative correlation with macrophages. Furthermore, we found PHLDA1 to be downregulated in an in vitro hepatic steatosis cell model, and overexpression of PHLDA1 significantly reduced lipid accumulation, as well as the expression of key molecules involved in hepatic lipogenesis and fatty acid uptake, such as FASN, SCD-1, and CD36. Additionally, gene set enrichment analysis (GSEA) pathway enrichment analysis suggested that PHLDA1 may influence NAFLD progression through pathways such as Cytokine Cytokine Receptor Interaction, Ecm Receptor Interaction, Parkinson's Disease, and Ribosome pathways. Our conclusions were further validated in a mouse model of NAFLD. Our study reveals that PHLDA1 inhibits the progression of NAFLD, as overexpression of PHLDA1 significantly reduces lipid accumulation in cells and markedly decreases the expression of key molecules involved in liver lipogenesis and fatty acid uptake. Therefore, PHLDA1 may emerge as a novel potential target for future prediction, diagnosis, and targeted prevention of NAFLD.

Models incorporating physical, laboratory and gut metabolite markers can be used to predict severe hepatic steatosis in MAFLD patients.

Metabolic-associated fatty liver disease (MAFLD) induced-severe hepatic steatosis poses significant health risks. Early prediction of this condition is crucial for prompt intervention. Short-chain fatty acids (SCFAs) and tryptophan are gut metabolites correlated with MAFLD pathogenesis in the gut-liver axis. This study aims to construct prediction models for severe hepatic steatosis by including SCFAs and tryptophan metabolites. This study enrolled 83 participants from the outpatient department in 2023. Physical measurements, serum metabolic and inflammatory markers, metabolites of serum SCFAs and tryptophan were collected. Severe hepatic steatosis was diagnosed using vibration-controlled transient elastography and abdominal sonography. All 40 (48.2%) participants diagnosed with severe hepatic steatosis had MAFLD, while approximately three-quarters of those without severe hepatic steatosis had MAFLD. In comparison to the non-severe hepatic steatosis group, individuals with severe hepatic steatosis exhibited higher levels of waist and arm circumference, serum triglyceride (TG), and lower levels of serum high-density lipoprotein cholesterol (HDL-C) and AST/ALT ratio. They also had higher serum levels of lipopolysaccharide-binding protein, isovaleric acid, and propionic acid, and lower levels of 3-methylvaleric acid, indole-3-propionic acid, and indoxyl sulfate. Models incorporating these markers predicted severe hepatic steatosis. One model additionally included waist circumference and triglyceride-glucose index, while the other incorporated arm circumference and TG/HDL-C ratio. The area under the curve reached 0.958 and 0.938, respectively (p < 0.001). SCFAs and tryptophan metabolites are valuable in predicting severe hepatic steatosis. Further research is needed to investigate the roles of these metabolites in MAFLD.

Conceptual study of Non-Alcoholic Fatty Liver Disease and its management in Ayurveda

Non-alcoholic Fatty liver Disease (NAFLD) is a condition with excessive fat deposition in liver on refers to a broad spectrum of disorders characterized by fatty infiltration of the liver steatosis, steatohepatitis and cirrhosis. It is a growing cause of liver injury globally and is present in developed and developing countries. NAFLD is a broad term which describes the build up of excessive fat in the liver cells (hepatocytes) in the absence of excessive alcohol intake. It is a growing worldwide, due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. NAFLD encompasses a spectrum of liver Pathology with different clinical prognoses, from the simple accumulation of triglycerides within hepatocytes to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis and in some cases hepatocellular Carcinoma. It is a global epidemic that ranges from isolated hepatic steatosis (NAFL) to Steatosis Plus inflammation (NASH) with or without fibrosis. Ayurveda described different types of Non-Communicable diseases, and NAFLD is one among them. In Ayurveda NAFLD can be interpreted as a Santarpanotha Vikara caused by Kapha Medo Dushti, getting Sthanasamshraya in Yakrit, which is Raktavaha Srotasmula and Pittasthana. In the initial stage of NAFLD, Kapha Meda Dushti occurs when Pitta gets involved in the pathogenesis, inflammatory changes occur which leads to the next stage of disease i.e., Non alcoholic steatohepatitis (NASH), When Vata comes involved fibrosis occurs which may end up in cirrhosis. So, the management should be the breakdown of pathological factors like Agnivaigunya, Srotorodha and Kaphamedo Dushti. This review will give a better knowledge of etiopathogenesis.

Integrative Analyses of Genes of Pediatric Non-alcoholic Fatty Liver Disease Associated with Energy Metabolism.

Pediatric non-alcoholic fatty liver disease (NAFLD) is a chronic steatosis of the liver associated with energy metabolism in children and adolescents, failure to intervene promptly can elevate the risk of developing hepatocellular carcinoma. Therefore, this study aimed to understand the underlying mechanism of pediatric NAFLD and investigate potential biomarkers and therapeutic targets. We investigated genes using the GSE185051 data set related to energy metabolism from the GeneCards database, constructed protein-protein interaction network, identified hub genes and established networks representing interactions between these hub genes and miRNA, RNA-binding proteins, transcription factors, and drugs. Subsequently, we performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, Gene Set Enrichment Analysis (GSEA), and immune infiltration analysis. Our analysis identified 9 hub genes through the PPI network. The target molecules were identified through the interaction network between hub genes and miRNAs, RNA-binding proteins, transcription factors, and drugs. GO analysis revealed that hub genes were associated with oxidative stress responses and other pathways. KEGG analysis highlighted their involvement in pathways such as insulin resistance, among others. GSEA revealed that hub genes were highly enriched in pathways related to Omega-9 fatty acid synthesis, among others. Immune infiltration analysis suggested that mast cells and T follicular helper cells play significant roles in the pathogenesis of NAFLD. We identified the hub genes in pediatric NAFLD closely related to energy metabolism. These findings offer the potential for identifying potential novel diagnostic biomarkers, and establishing therapeutic targets for pediatric NAFLD.

The Impact of Combined Cranberry Supplementation and Weight Loss Diet on Inflammatory, Antioxidant, and Apoptosis Biomarkers in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized, Double-Blinded, Controlled Clinical Trial

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The aim of this study is to evaluate the effect of combined weight loss diet and cranberry supplementation on anthropometric measurements, inflammation and antioxidant biomarkers in patients with NAFLD. Methods: In this randomized, double-blinded, and controlled clinical trial, 41 NAFLD patients were supplemented with either cranberry or placebo tablets for 12 weeks. Both groups followed a diet of 500-1000 calories less than the estimated energy requirements. Serum levels of total antioxidant capacity (TAC), malondialdehyde (MDA), cytokeratin 18 M30 (CK-18 M30), chemokine C-C motif ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α) were measured at both baseline and the end of the study. Results: Significant improvements in TAC were observed in the cranberry group and between the two groups (P=0.006 and P=0.011, respectively), but the changes in the placebo group were not significant (P=0.325). There were no statistically significant differences in the serum levels of MDA, CK-18 M30, CCL2 and TNF-α between the cranberry and the placebo groups (P&gt;0.05). Conclusions: It seems that daily consumption of cranberry supplement would be beneficial in increasing serum levels of TAC. Further studies are needed to investigate the effects of anti-inflammatory and antioxidant properties of cranberry on NAFLD.