Pathogenesis Of Nonalcoholic Fatty Liver Disease Research Articles

Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients

BACKGROUND The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophysiology of NAFLD in T2DM. AIM To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. METHODS A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. RESULTS Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. CONCLUSION This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.

Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine

ABSTRACT Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Six-gene prognostic signature for non-alcoholic fatty liver disease susceptibility using machine learning.

nonalcoholic fatty liver disease (NAFLD) is a common liver disease affecting the global population and its impact on human health will continue to increase. Genetic susceptibility is an important factor influencing its onset and progression, and there is a lack of reliable methods to predict the susceptibility of normal populations to NAFLD using appropriate genes. RNA sequencing data relating to nonalcoholic fatty liver disease was analyzed using the "limma" package within the R software. Differentially expressed genes were obtained through preliminary intersection screening. Core genes were analyzed and obtained by establishing and comparing 4 machine learning models, then a prediction model for NAFLD was constructed. The effectiveness of the model was then evaluated, and its applicability and reliability verified. Finally, we conducted further gene correlation analysis, analysis of biological function and analysis of immune infiltration. By comparing 4 machine learning algorithms, we identified SVM as the optimal model, with the first 6 genes (CD247, S100A9, CSF3R, DIP2C, OXCT 2 and PRAMEF16) as predictive genes. The nomogram was found to have good reliability and effectiveness. Six genes' receiver operating characteristic curves (ROC) suggest an essential role in NAFLD pathogenesis, and they exhibit a high predictive value. Further analysis of immunology demonstrated that these 6 genes were closely connected to various immune cells and pathways. This study has successfully constructed an advanced and reliable prediction model based on 6 diagnostic gene markers to predict the susceptibility of normal populations to NAFLD, while also providing insights for potential targeted therapies.

Exploring the interconnected between type 2 diabetes mellitus and nonalcoholic fatty liver disease: Genetic correlation and Mendelian randomization analysis.

Epidemiological and clinical studies have indicated a higher risk of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), implying a potentially shared genetic etiology, which is still less explored. Genetic links between T2DM and NAFLD were assessed using linkage disequilibrium score regression and pleiotropic analysis under composite null hypothesis. European GWAS data have identified shared genes, whereas SNP-level pleiotropic analysis under composite null hypothesis has explored pleiotropic loci. generalized gene-set analysis of GWAS data determines pleiotropic pathways and tissue enrichment using eQTL mapping to identify associated genes. Mendelian randomization analysis was used to investigate the causal relationship between NAFLD and T2DM. Linkage disequilibrium score regression analysis revealed a strong genetic correlation between T2DM and NAFLD, and identified 24 pleiotropic loci. These single-nucleotide polymorphisms are primarily involved in biosynthetic regulation, RNA biosynthesis, and pancreatic development. generalized gene-set analysis of GWAS data analysis revealed significant enrichment in multiple brain tissues. Gene mapping using these 3 methods led to the identification of numerous pleiotropic genes, with differences observed in liver and kidney tissues. These genes were mainly enriched in pancreas, brain, and liver tissues. The Mendelian randomization method indicated a significantly positive unidirectional causal relationship between T2DM and NAFLD. Our study identified a shared genetic structure between NAFLD and T2DM, providing new insights into the genetic pathogenesis and mechanisms of NAFLD and T2DM comorbidities.

The Association between Dietary Polyphenol and Non-Alcoholic Fatty Liver Disease Risk in Adults: A Systematic Review and Meta-Analysis of Observational Studies

Background: Non-alcoholic fatty liver disease (NAFLD) is regarded as a global health issue with increasing prevalence worldwide. Polyphenols play a pivotal role in alleviating inflammatory and oxidative stress pathways associated with the pathogenesis of NAFLD, however the literature are still scarce. Methods: This systematic review and meta-analysis was designed to investigate the association between dietary polyphenols and the risk of NAFLD with a meta-analysis approach. All observational studies in the online databases of PubMed, Scopus, Web of Science, Embase and Google Scholar up to June 2021 were searched, determining appropriate keywords, to identify relevant articles. Data were summarized using risk ratios (RRs) with 95% confidence intervals (CIs). Results: Of the total number of 4144 articles identified in the first phase of the literature search, 6 studies covering 21 arms on polyphenol intake and NAFLD risk containing 9436 participants in the case groups and 19996 participants in the control groups were included in study. The summary effect size (ES) for the risk of NAFLD, comparing the highest with lowest intakes of polyphenol, was 0.80 (95% CI: 0.77-0.83, P<0.0001, I2 = 0.0%;), indicating a significant inverse association. Conclusions: Our results proved that higher dietary intake of polyphenols can reduce the risk of NAFLD. However, due to small number of determined studies, these findings require further investigations to confirm recommendations for intensifying polyphenol intake in the general population.

Neurotensin receptor‐1 antagonist SR48692 modulation of high‐fat diet–induced pathogenesis of NAFLD in mice

AbstractThis study investigates the efficacy of the antagonist of neurotensin receptor‐1 (NTSR1) SR48692 in modulating the high‐fat diet (HFD)‐induced nonalcoholic fatty liver disease (NAFLD). HFD increases NTS secretion, which enhances fat absorption from the gastrointestinal tract (GIT) via receptors NTSR1/NTSR2/NTSR3. Absorbed fat from the GIT via hepatic‐portal system reaches the liver, where it gets accumulated to cause NAFLD. Swiss albino mice (8 weeks) were maintained in two batches fed standard diet (SD) and HFD for 4 weeks, then divided into six groups: Group I (SD) and Group II (HFD) administered intraperitoneally 0.9% saline (vehicle), Group III: low dose of antagonist (100 µg kg−1 bw: HFD+SR48692L), Group IV: high dose (400 µg kg−1 bw: HFD+SR48692H), Group V (SD+SR48692L), and Group VI (SD+SR48692H). SR48692L treatment in HFD‐fed mice showed partial efficacy in preventing lipid absorption and reducing oxidative stress, as reflected in histology and plasma transaminases. Contrarily, with SR48692H dose, the effects were detrimental. Involvement of other signaling pathways (NTS‐NTSR2, NTS‐NTSR3) in lipid absorption might be the reason of partial efficacy. The adverse effects with the SR48692H might be due to the differential dose–response effect of the antagonist.Practical Application: HFD‐induced hyperlipidemia and NAFLD are linked to enhanced NTS secretion. As NTS enhances fat absorption, blocking its receptors with antagonists might provide efficacy against HFD‐induced NAFLD. This study with NTSR1 antagonist SR48692 provides some evidence of its in preventing hyperlipidemia; further studies targeting other receptors (NTSR2, NTSR3) are essential for understanding the therapeutic efficacy of the NTS antagonists for NAFLD.

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

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

Global Trends of Treatment for NAFLD from 2012 to 2021: A Bibliometric and Mapping Analysis.

The present study aimed to map publication trends and explore research hotspots of treatment for NAFLD study by bibliometric analysis. Nonalcoholic fatty liver disease (NAFLD) is a multi-system metabolic disorder involving the liver. Thousands of papers have been published on the treatment of NAFLD, but no comprehensive statistical and intuitive analysis has been made. The present study aimed to map publication trends and explore research hotspots of treatment for NAFLD study by biblio-metric analysis. (1) the pathogenesis of NAFLD and the possible treatment mechanism; (2) preva-lence, risk factors, and traditional therapies for NAFLD; (3) frontier therapies for NAFLD. Method; This paper conducted a bibliometric analysis based on the Web of Science Core Col-lection (WoSCC). The knowledge map was constructed by VOS viewer v.1.6.10 to visualize the annual publication number, the distribution of countries, international collaborations, author productivity, source journals, cited references, and keywords in this field. From 2012 to 2021, 2,437 peer-reviewed publications on the treatment of NAFLD were retrieved. China contributed the most publications, while the United States received the most citations. Journal of Hepatology was the most prolific journal in this field. Prof. Rohit Loomba. Our study provides a comprehensive and objective analysis of NAFLD treatment that allows researchers to quickly locate research hotspots in a large number of relevant litera-tures. Meanwhile, it may also provide valuable information for researchers looking for potential partners and institutions.

Identification and validation of cuproptosis-related genes for diagnosis and therapy in nonalcoholic fatty liver disease.

In recent years, nonalcoholic fatty liver disease (NAFLD) has become a more serious public health issue worldwide. This study strived to investigate the molecular mechanism of pathogenesis of NAFLD and explore promising diagnostic and therapeutic targets for NAFLD. Raw data from GSE130970 were downloaded from the Gene Expression Omnibus database. We used the dataset to analyze the expression levels of cuproptosis-related genes in NAFLD patients and healthy controls to identify the differentially expressed cuproptosis-related genes (DECRGs). The relationship and potential mechanism between DECRGs and clinicopathological factors were examined by enrichment analysis and two consensus clustering methods. We screened key DECRGs based on Random Forest (RF), and then verified the key DECRGs in NAFLD patients, high-fat diet (HFD)-fed mice, and palmitic acid-induced AML12 cells. ROC analysis showed good diagnostic function of DECRGs in normal and NAFLD liver tissue. Two consensus clusters indicated the important role of cuproptosis in the development of NAFLD. We screened for key DECRGs (DLD, DLAT) based on RF and found a close relationship between the DECRGs and clinicopathological factors. We collected clinical blood samples to verify the differences in gene expression levels by qPCR. In addition, we further verified the expression levels of DLD and DLAT in HFD mice and AML12 cells, which showed the same results. This study provides a novel perspective on the pathogenesis of NAFLD. We identified two cuproptosis-related genes that are closely related to NAFLD. These genes may play a significant role in the molecular pathogenesis of NAFLD, which may be useful to make progress in the diagnosis and treatment of NAFLD.

Bacteroides and NAFLD: pathophysiology and therapy.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition observed globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Currently, the US Food and Drug Administration (FDA) has not approved any drugs for the treatment of NAFLD. NAFLD is characterized by histopathological abnormalities in the liver, such as lipid accumulation, steatosis, hepatic balloon degeneration, and inflammation. Dysbiosis of the gut microbiota and its metabolites significantly contribute to the initiation and advancement of NAFLD. Bacteroides, a potential probiotic, has shown strong potential in preventing the onset and progression of NAFLD. However, the precise mechanism by which Bacteroides treats NAFLD remains uncertain. In this review, we explore the current understanding of the role of Bacteroides and its metabolites in the treatment of NAFLD, focusing on their ability to reduce liver inflammation, mitigate hepatic steatosis, and enhance intestinal barrier function. Additionally, we summarize how Bacteroides alleviates pathological changes by restoring the metabolism, improving insulin resistance, regulating cytokines, and promoting tight-junctions. A deeper comprehension of the mechanisms through which Bacteroides is involved in the pathogenesis of NAFLD should aid the development of innovative drugs targeting NAFLD.

Anti-osteoporotic treatments in the era of non-alcoholic fatty liver disease: friend or foe.

Over the last years non-alcoholic fatty liver disease (NAFLD) has grown into the most common chronic liver disease globally, affecting 17-38% of the general population and 50-75% of patients with obesity and/or type 2 diabetes mellitus (T2DM). NAFLD encompasses a spectrum of chronic liver diseases, ranging from simple steatosis (non-alcoholic fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH; or metabolic dysfunction-associated steatohepatitis, MASH) to fibrosis and cirrhosis with liver failure or/and hepatocellular carcinoma. Due to its increasing prevalence and associated morbidity and mortality, the disease-related and broader socioeconomic burden of NAFLD is substantial. Of note, currently there is no globally approved pharmacotherapy for NAFLD. Similar to NAFLD, osteoporosis constitutes also a silent disease, until an osteoporotic fracture occurs, which poses a markedly significant disease and socioeconomic burden. Increasing emerging data have recently highlighted links between NAFLD and osteoporosis, linking the pathogenesis of NAFLD with the process of bone remodeling. However, clinical studies are still limited demonstrating this associative relationship, while more evidence is needed towards discovering potential causative links. Since these two chronic diseases frequently co-exist, there are data suggesting that anti-osteoporosis treatments may affect NAFLD progression by impacting on its pathogenetic mechanisms. In the present review, we present on overview of the current understanding of the liver-bone cross talk and summarize the experimental and clinical evidence correlating NAFLD and osteoporosis, focusing on the possible effects of anti-osteoporotic drugs on NAFLD.

Non-alcoholic fatty liver disease and Helicobacter pylori infection: is there a relationship? Review

The article outlines the relevance of finding a connection between non‑alcoholic fatty liver disease (NAFLD) and Helicobacter pylori infection. The presented data of the majority of studies indicate the presence of Helicobacter pylori infection as a risk factor for the development of NAFLD. In addition, a number of researchers point to the possibility of the influence of Helicobacter pylori on important pathogenetic chains of NAFLD: insulin resistance, the state of the intestinal microbiota, the level of such hormones as ghrelin, leptin, adiponectin, and also that the effect of Helicobacter pylori (H. pylori) toxins can cause direct damage to the liver and that Helicobacter pylori invasion of the small intestine mucosa can increase the permeability of the latter, disrupting the functioning of the gut—liver axis. The article emphasizes the relationship between H. pylori infection and an unfavorable metabolic profile: dyslipidemia, body mass index, blood pressure, fasting blood glucose, and insulin resistance. In addition, research data on the novelty of higher levels of aspartate and alanine aminotransferase in Helicobacter‑positive patients compared to Helicobacter‑negative patients, in the absence of differences in liver fibrosis, are given. Separately, the research data are given, which indicate that the successful eradication of Helicobacter infection does not have a significant effect on liver steatosis, but probably reduces the severity of insulin resistance. Also, the authors draw attention to the fact that in a number of studies, the connection of H. pylori with NAFLD was not found, and no significant differences were found in the levels of high and low‑density lipoprotein cholesterol in people with Helicobacter infection compared to Helicobacter‑negative ones. The authors conclude that today there is no clear understanding of the role of Helicobacter pylori infection in the NAFLD pathogenesis, which requires further research because, after all, most researchers testify in favor of the fact that H. pylori infection can be one of the risk factors, contributing to the emergence and progression of NAFLD, and eradication of H. pylori may be important in the treatment of this disease.  

Nanoplastics and chrysene pollution: Potential new triggers for nonalcoholic fatty liver disease and hepatitis, insights from juvenile Siniperca chuatsi

Nanopolystyrene (NP) and chrysene (CHR) are ubiquitous contaminants in the natural environment; however, research on their hepatotoxicity and associated adverse effects remains relatively inadequate. The present study aimed to investigate the hepatotoxic effects of NP and/or CHR at environmentally relevant concentrations, as well as the underlying molecular mechanisms, in juvenile Siniperca chuatsi (mandarin fish). After a 21-day exposure period, the livers of exposed S. chuatsi exhibited macrostructural and microstructural damage accompanied by oxidative stress. Importantly, our study provides the first evidence that NP exposure leads to the development of nonalcoholic fatty liver disease (NAFLD) and hepatitis in S. chuatsi. Similarly, CHR exposure has also been found, for the first time, to cause hepatic sinusoidal dilatation (HSD) and hepatitis. Exposure to the combination of NP and CHR alleviated the symptoms of NAFLD, HSD, and hepatitis. Furthermore, our comprehensive multi-omic analysis revealed that the pathogenesis of NP-induced NAFLD was mainly due to induction of the triglyceride synthesis pathway and inhibition of the very-low-density lipoprotein secretion process. CHR induced HSD primarily through a reduction in vasoprotective ability and smooth muscle contractility. Hepatitis was induced by activation of the JAK-STAT/NF-kappa B signaling pathways, which upregulated the expression of inflammation-specific genes. Collectively, results of this study offer novel insight into the multiple hepatotoxicity endpoints of NP and/or CHR exposure at environmentally relevant concentrations in organisms, and highlight the importance of nanoplastic/CHR pollution for liver health.

PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine-induced hepatic steatosis via both receptor-dependent and receptor-independent pathways.

Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine-induced NAFLD. C57BL/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs invitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor-dependent pathways (impacting NPC1L1) and receptor-independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP-1c, rather than SREBP-2, was identified as a key driver of PCSK9 increase in olanzapine-induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine-induced NAFLD, influencing both receptor-related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.

Exploration of the Key Genes Involved in Non-alcoholic Fatty Liver Disease and Possible MicroRNA Therapeutic Targets

BackgroundMicroRNAs (miRNAs) are promising therapeutic agents for nonalcoholic fatty liver disease (NAFLD). This study aimed to identify key genes/proteins involved in NAFLD pathogenesis and progression and to evaluate miRNAs influencing their expression. MethodsGene expression profiles from datasets GSE151158, GSE163211, GSE135251, GSE167523, GSE46300 and online databases were analyzed to identify significant NAFLD-related genes. Then, protein-protein interaction networks and module analysis identified hub genes/proteins, which were validated using real-time PCR in oleic acid-treated HepG2 cells. Functional enrichment analysis evaluated signaling pathways and biological processes. Gene-miRNA interaction networks identified miRNAs targeting critical NAFLD genes. ResultsThe most critical overexpressed hub genes/proteins included: TNF, VEGFA, TLR4, CYP2E1, ACE, SCD, FASN, SREBF2 and TGFB1 based on PPI network analysis, of which TNF, TLR4, SCD, FASN, SREBF2 and TGFB1 were up-regulated in oleic acid-treated HepG2 cells. Functional enrichment analysis for biological processes highlighted programmed necrotic cell death, lipid metabolic process response to reactive oxygen species, and inflammation. In Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the highest adjusted P-value signaling pathways encompassed AGE-RAGE in diabetic complications, TNF and HIF-1 signaling pathways. In gene-miRNA network analysis, miR-16 and miR-124 were highlighted as the miRNAs exerting the most influence on important NAFLD-related genes. ConclusionIn silico analyses identified NAFLD therapeutic targets and miRNA candidates to guide further experimental investigation.

Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients.

Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non-alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross-validation approach to assess this interaction in bariatric patients. 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non-alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4. We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3-F4) versus F0 had lower abundance of anti-inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol-10 biosynthesis and Peptidoglycan biosynthesis IV. In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity.

Non-alcoholic fatty liver disease: pathogenesis and assessing the impact of dietary bioactive compounds

Non-alcoholic fatty liver disease (NAFLD) is a pathological condition ranging from simple steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer. NAFLD is a complex disease mediated by metabolic, environmental, and genetic mechanisms. Many factors such as insulin resistance, lipotoxicity, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress, circadian rhythm, genetics, epigenetics, dietary factors, and gut microbiota play a crucial role in the pathogenesis of NAFLD. Lifestyle changes such as healthy diet, physical activity, avoiding alcohol and smoking are involved in the NAFLD treatment. Dietary bioactive compounds including curcumin, resveratrol, catechins, quercetin, sulforaphane, epigallocatechin-3-gallate, alkaloids, vitamins, and peptides have many health promoting effects such as antioxidant, anti-inflammatory, antihypertensive, chemopreventive, and hepatoprotective. In this review, the pathophysiology of NAFLD and the effects of dietary bioactive compounds on this disease will be discussed in detail with updated information.

Molecular Insights of Nonalcoholic Fatty Liver Disease Pathogenesis.

Nonalcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease. Many hepatic abnormalities are associated with NAFLD such as nonalcoholic steatohepatitis, progressive fibrosis, cirrhosis, and liver failure. Moreover, the pathogenesis of NAFLD has numerous etiologies and can be explained due to the existence of several of stimulus that act simultaneously on genetically susceptible patients. These stimuli include obesity, diabetes, and insulin resistance. In addition, identifying the role of gut microbiota on NAFLD progression has been illustrated. In this review, we clarified the several factors that lead to the development of NAFLD and identify those who are most at risk of developing liver end-stage disease. Highlighting the noninvasive diagnostic NAFLD markers could be helpful in the disease prevention and treatment approaches.

Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways.

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.

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

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