Pathogenesis Of Nonalcoholic Fatty Liver Disease Research Articles

Saccharomyces boulardii Mitigates Fructose-Induced Non-Alcoholic Fatty Liver in Rats.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern closely linked to metabolic disorders, including obesity, insulin resistance, and dyslipidemia. Emerging evidence suggests that the gut-liver axis plays a critical role in the pathogenesis of NAFLD, with recent research highlighting the influence of gut microbiota, including fungal species such as Saccharomyces boulardii (S. boulardii). This study aimed to evaluate the effects of S. boulardii on lipid metabolism and oxidative stress in a rat model of fructose-induced NAFLD. Materials and Methods: Thirty Wistar rats were divided into three groups: a control group, a fatty liver group induced by 35% fructose supplementation, and a treatment group receiving S. boulardii (100 mg/kg/day) after fructose induction. Results: Biochemical analyses revealed that the treatment group exhibited significantly lower plasma levels of malondialdehyde (MDA), alanine aminotransferase (ALT), total triglycerides, and cholesterol compared to the untreated fatty liver group (p < 0.05). Furthermore, liver tissue analysis showed a marked reduction in lipid accumulation and fatty infiltration in the treatment group, with no visible lipid vacuoles in hepatocytes. The expression of aquaporin-8 (AQP8) and sirtuin-1 (SIRT1), key markers associated with hepatocyte function and lipid metabolism, was significantly higher in the S. boulardii group compared to the fatty liver group (p < 0.001). Conclusions: These findings indicate that S. boulardii supplementation mitigates the metabolic and oxidative stress-related alterations associated with fructose-induced NAFLD. In conclusion, our study suggests that S. boulardii exerts protective effects on the liver by reducing lipid accumulation and oxidative stress, highlighting its potential as a therapeutic intervention for NAFLD.

6428 Update on Genetic F6428 actors of Nonalcoholic Fatty Liver Disease

Abstract Disclosure: H.M. Heshmati: None. Background: Nonalcoholic fatty liver disease (NAFLD) is a pandemic with a prevalence of 25% among the adult population worldwide. NAFLD is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and hepatocellular cancer. The pathogenesis of NAFLD is complex and multifactorial, involving metabolic, epigenetic, and genetic factors. Several medical conditions (e.g., obesity, type 2 diabetes, inflammation, insulin resistance, disrupted gut microbiome, and impaired intestinal barrier function) are important risk factors associated with and/or contributing to NAFLD. This review presents an update on the genetic factors of NAFLD identified by the genome-wide association studies (GWAS). Methods: A systematic search of literature was conducted using the search terms nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, hepatocellular cancer, obesity, type 2 diabetes, epigenetics, and genetics. Results: Evidence for the contribution of genetic factors to NAFLD is further emphasized by the ethnic differences in the prevalence of NAFLD (e.g., higher prevalence among Hispanic American compared to African American adults). Based on the results of the GWAS, several genetic modifiers are relevant to NAFLD development and progression. They include variations in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7), glucokinase regulatory protein (GCKR), programmed cell death protein 1 (PDCD1), and hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) genes (non-exhaustive list). These genetic modifiers interact with the metabolic and epigenetic factors for the development and progression of NAFLD and are responsible for the variability in the severity of NAFLD. The PNPLA3 gene variant (rs738409), which is the first and the best validated genetic modifier, is associated with a high risk of development and progression of NAFLD. The PDCD1 gene variant (rs7421861) is independently associated with hepatocellular cancer development. In contrast, the HSD17B13 gene variant (rs72613567) may have a protective effect for NAFLD risk. Conclusion: NAFLD is a multifactorial condition with a complex pathogenesis involving the interactions between metabolic, epigenetic, and genetic factors. The prevalence and risk of NAFLD differ across populations mainly due to genetic polymorphisms. Genetic factors relevant to NAFLD include variations in PNPLA3, TM6SF2, MBOAT7, GCKR, PDCD1, and HSD17B13 genes. A better understanding of these genetic modifiers and their mechanisms of action should allow a better risk prediction of the development of NAFLD and its progression to cirrhosis and hepatocellular cancer and help the development of new and selected therapies for NAFLD. Presentation: 6/3/2024

Association between phthalates exposure and non-alcoholic fatty liver disease under different diagnostic criteria: a cross-sectional study based on NHANES 2017 to 2018.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. Phthalates have been suggested to influence the development of NAFLD due to their endocrine-disrupting properties, but studies based on nationally representative populations are insufficient, and existing studies seem to have reached conflicting conclusions. Due to changes in legislation, the use of traditional phthalates has gradually decreased, and the phthalates substitutes is getting more attention. This study aims to delve deeper into how the choice of diagnostic approach influences observed correlations and concern about more alternatives of phthalates, thereby offering more precise references for the prevention and treatment of NAFLD. A cohort of 641 participants, sourced from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 database, was evaluated for NAFLD using three diagnostic methods: the Hepatic Steatosis Index (HSI), the US Fatty Liver Indicator (US.FLI), and Vibration Controlled Transient Elastography (VCTE). The urinary metabolite concentrations of Di-2-ethylhexyl phthalate (DEHP), Di-isodecyl phthalate (DIDP), Di-isononyl phthalate (DINP), Di-n-butyl phthalate (DnBP), Di-isobutyl phthalate (DIBP), Di-ethyl phthalate (DEP) and Di-n-octyl phthalate (DnOP) were detected. The association between NAFLD and urinary phthalate metabolites was evaluated through univariate and multivariate logistic regression analyses, considering different concentration gradients of urinary phthalates. Univariate logistic regression analysis found significant correlations between NAFLD and specific urinary phthalate metabolites, such as Mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), Mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and Mono-(carboxyisoctyl) phthalate (MCiOP), across different diagnostic criteria. In a multivariate logistic regression analysis adjusting only for demographic data, MEOHP (OR = 3.26, 95% CI = 1.19-8.94, p = 0.029), MEHHP (OR = 3.98, 95% CI = 1.43-11.1, p = 0.016), MECPP (OR = 3.52, 95% CI = 1.01-12.2, p = 0.049), and MCiOP (OR = 4.55, 95% CI = 1.93-10.7, p = 0.005) were positively related to NAFLD defined by HSI and VCTE. The correlation strength varied with the concentration of phthalates, indicating a potential dose-response relationship. Adjusting for all covariates in multivariate logistic regression, only MCiOP (OR = 4.22, 95% CI = 1.10-16.2, p = 0.044), as an oxidative metabolite of DINP, remained significantly associated with NAFLD under the VCTE criterion, suggesting its potential role as a risk factor for NAFLD. This research highlights a significant association between DINP and NAFLD. These findings underscore the need for further investigation into the role of the phthalates substitutes in the pathogenesis of NAFLD and the importance of considering different diagnostic criteria in research.

Probiotics and Non-Alcoholic Fatty Liver Disease: Unveiling the Mechanisms of Lactobacillus plantarum and Bifidobacterium bifidum in Modulating Lipid Metabolism, Inflammation, and Intestinal Barrier Integrity.

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen annually, yet due to the intricacies of its pathogenesis and therapeutic challenges, there remains no definitive medication for this condition. This review explores the intricate relationship between the intestinal microbiome and the pathogenesis of NAFLD, emphasizing the substantial roles played by Lactobacillus plantarum and Bifidobacterium bifidum. These probiotics manipulate lipid synthesis genes and phosphorylated proteins through pathways such as the AMPK/Nrf2, LPS-TLR4-NF-κB, AMPKα/PGC-1α, SREBP-1/FAS, and SREBP-1/ACC signaling pathways to reduce hepatic lipid accumulation and oxidative stress, key components of NAFLD progression. By modifying the intestinal microbial composition and abundance, they combat the overgrowth of harmful bacteria, alleviating the inflammatory response precipitated by dysbiosis and bolstering the intestinal mucosal barrier. Furthermore, they participate in cellular immune regulation, including CD4+ T cells and Treg cells, to suppress systemic inflammation. L. plantarum and B. bifidum also modulate lipid metabolism and immune reactions by adjusting gut metabolites, including propionic and butyric acids, which inhibit liver inflammation and fat deposition. The capacity of probiotics to modulate lipid metabolism, immune responses, and gut microbiota presents an innovative therapeutic strategy. With a global increase in NAFLD prevalence, these insights propose a promising natural method to decelerate disease progression, avert liver damage, and tackle associated metabolic issues, significantly advancing microbiome-focused treatments for NAFLD.

The association of food insecurity with non-alcoholic fatty liver disease (NAFLD) in a sample of Iranian adults: a path analysis of a cross-sectional survey

ObjectivesThe present study aims to examine the hypothetical model of the relationship between food insecurity and Non-alcoholic fatty liver disease (NAFLD) in a sample of Iranian adults.MethodsIn this cross-sectional study, 275 subjects (18–70 years old) who met the inclusion criteria were recruited. Fatty liver was diagnosed by abdominal ultrasonography, and eligible patients underwent liver fibro scan assessment to determine fibrosis and steatosis. Food insecurity was assessed using the validated six-item Short Questionnaire of Household Food Security Scale (SQHFSS). Data were analyzed using SPSS 24.0 and IBM SPSS Amos 24.0.ResultsAmong 275 subjects (44.37 ± 11.67 years old, 51.6% male) included in the analysis, 23.6% were food insecure. Food insecurity, general and abdominal obesity were associated with an increased risk of NAFLD, even after multiple adjustments (OR: 2.95, 95% CI: 1.02, 8.57; OR: 3.27, 95% CI: 1.50, 7.11; and OR: 3.81, 95% CI: 1.55, 9.32, respectively). According to the primary hypothesis, food insecurity and NAFLD were fitted into a model (χ2/df = 1.36, GFI = 0.982, AGFI = 0.952, CFI = 0.954, IFI = 0.959, SRMR = 0.040, RMSEA = 0.037); accordingly, food insecurity and obesity (general and abdominal) directly affected NAFLD (β = 0.12, P = 0.03; β = 0.13, P = 0.02; β = 0.31, P < 0.001, respectively).ConclusionFood insecurity was a predictor of, and directly associated with, NAFLD. Social determinants should be considered in the pathogenesis of NAFLD, although the possible underlying biological mechanisms in this association are yet to be determined.

Highly sensitive near-infrared fluorescent probe for monitoring peroxynitrite in nonalcoholic fatty liver disease: Toward early diagnosis and therapeutic evaluation

Nonalcoholic fatty liver disease (NAFLD) poses a significant global health concern, necessitating precise diagnostic tools and effective treatment strategies. Peroxynitrite (ONOO−), a reactive oxygen species, plays a pivotal role in NAFLD pathogenesis, highlighting its potential as a biomarker for disease diagnosis and therapeutic evaluation. This study reports on the development of a near-infrared (NIR) fluorescent probe, designated DRP-O, for the selective detection of ONOO− with high sensitivity and photostability. DRP-O exhibits rapid response kinetics (within 2 min) and an impressive detection limit of 2.3 nM, enabling real-time monitoring of ONOO− dynamics in living cells. Notably, DRP-O demonstrates excellent photostability under continuous laser irradiation, ensuring reliable long-term monitoring in complex biological systems. We apply DRP-O to visualize endogenous ONOO− in living cells, demonstrating its potential for diagnosing and monitoring NAFLD-related oxidative stress. Furthermore, DRP-O effectively evaluates the efficacy of therapeutic drugs in NAFLD cell models, underscoring its potential utility in drug screening studies. Moreover, we confirm DRP-O to enable selective identification of fatty liver tissues in a mouse model of NAFLD, indicating its potential for the early diagnosis of NAFLD. Collectively, DRP-O represents a valuable tool for studying ONOO− dynamics, evaluating drug efficacy, and diagnosing NAFLD, offering insights into novel therapeutic strategies for this prevalent liver disorder.

Identification of neutrophil extracellular trap-related biomarkers in non-alcoholic fatty liver disease through machine learning and single-cell analysis

Non-alcoholic Fatty Liver Disease (NAFLD), noted for its widespread prevalence among adults, has become the leading chronic liver condition globally. Simultaneously, the annual disease burden, particularly liver cirrhosis caused by NAFLD, has increased significantly. Neutrophil Extracellular Traps (NETs) play a crucial role in the progression of this disease and are key to the pathogenesis of NAFLD. However, research into the specific roles of NETs-related genes in NAFLD is still a field requiring thorough investigation. Utilizing techniques like AddModuleScore, ssGSEA, and WGCNA, our team conducted gene screening to identify the genes linked to NETs in both single-cell and bulk transcriptomics. Using algorithms including Random Forest, Support Vector Machine, Least Absolute Shrinkage, and Selection Operator, we identified ZFP36L2 and PHLDA1 as key hub genes. The pivotal role of these genes in NAFLD diagnosis was confirmed using the training dataset GSE164760. This study identified 116 genes linked to NETs across single-cell and bulk transcriptomic analyses. These genes demonstrated enrichment in immune and metabolic pathways. Additionally, two NETs-related hub genes, PHLDA1 and ZFP36L2, were selected through machine learning for integration into a prognostic model. These hub genes play roles in inflammatory and metabolic processes. scRNA-seq results showed variations in cellular communication among cells with different expression patterns of these key genes. In conclusion, this study explored the molecular characteristics of NETs-associated genes in NAFLD. It identified two potential biomarkers and analyzed their roles in the hepatic microenvironment. These discoveries could aid in NAFLD diagnosis and management, with the ultimate goal of enhancing patient outcomes.

Targeting mitochondrial homeostasis in the treatment of non-alcoholic fatty liver disease: a review.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence is rapidly increasing. Antioxidants, lipid-lowering medications, and lifestyle interventions are the most commonly used treatment options for NAFLD, but their efficacy in inhibiting steatosis progression is limited and their long-term ineffectiveness and adverse effects have been widely reported. Therefore, it is important to gain a deeper understanding of the pathogenesis of NAFLD and to identify more effective therapeutic approaches. Mitochondrial homeostasis governs cellular redox biology, lipid metabolism, and cell death, all of which are crucial to control hepatic function. Recent findings have indicated that disruption of mitochondrial homeostasis occurs in the early stage of NAFLD and mitochondrial dysfunction reinforces disease progression. In this review, we summarize the physical roles of the mitochondria and describe their response and dysfunction in the context of NAFLD. We also discuss the drug targets associated with the mitochondria that are currently in the clinical trial phase of exploration. From our findings, we hope that the mitochondria may be a promising therapeutic target for the treatment of NAFLD.

Effective roles of exercise and diet adherence in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by symptoms of excessive fat accumulation and steatosis in the liver without alcohol intake in patients. The associated pathogenic mechanism is not completely understood and there are no specific drugs for patients with NAFLD. Exercise and diet adherence are the best options for the management of NAFLD patients. Questionnaire associated analysis models of adherence to these interventions are used to assess their effectiveness in the management of NAFLD patients using specificity, sensitivity, and so on. Studies have indicated that the relative ratio of NAFLD can be reduced by physical activity with diet control. In the future, the pathogenesis of NAFLD should be clarified with stratified efforts to develop appropriate drugs, and both exercise and diet adherence should be optimized using better questionnaire design and evaluation models for patients with NAFLD.

Semaglutide Ameliorates Hepatocyte Steatosis in a Cell Co-Culture System by Downregulating the IRE1α-XBP1-C/EBPα Signaling Pathway in Macrophages.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common type of chronic liver disease. Semaglutide is a glucose-lowering drug administered for the treatment of type 2 diabetes mellitus (T2DM) and is clinically effective in the treatment of NAFLD. X-box binding protein 1 (XBP1) is related to the pathogenesis of both NAFLD and T2DM. The aim of the present study was to demonstrate whether the underlying mechanism of semaglutide treatment for NAFLD is via downregulation of the inositol-requiring transmembrane kinase/endonuclease-1α (IRE1α)-XBP1-CCAAT/enhancer binding protein α (C/EBPα) signaling pathway in macrophages. In the present study, NAFLD cell modeling was induced by oleic acid (0.4 m<sc>m</sc>) and palmitic acid (0.2 m<sc>m</sc>). Hepatocytes (AML12) and macrophages (RAW264.7) were co-cultured in 6-well Transwell plates. Semaglutide (60 or 140 n<sc>m</sc>) was administrated for 24 h, while pioglitazone (2 μ<sc>m</sc>) and toyocamycin (200 n<sc>m</sc>) were used as a positive control drug and a XBP1 inhibitor, respectively. Autophagy and apoptosis of AML12 cells were detected by transmission electron microscopy and Western blotting (WB). Hepatocyte steatosis was evaluated by adopting total intracellular triglyceride determination, analysis of the relative expression of proteins and genes associated with lipid metabolism and hepatocyte Oil red O staining. Detection of inflammation factors was conducted by ELISA and WB. To explore the underlying mechanism of NAFLD treatment with semaglutide, the relative expression of related proteins and genes were tested. Our study demonstrated that semaglutide treatment improved autophagy and inhibited apoptosis of hepatocytes, while notably ameliorating steatosis of hepatocytes. In addition, inflammation was attenuated in the NAFLD cell co-culture model after semaglutide administration. Semaglutide also significantly reduced the protein and gene expression levels of the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. Semaglutide partially ameliorated NAFLD by downregulating the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. These findings may provide a potential theoretical basis for semaglutide therapy for NAFLD.

Hepatic miR-363 promotes nonalcoholic fatty liver disease by suppressing INSIG1

Nonalcoholic fatty liver disease (NAFLD) constitutes one of major worldwide health problem which typically progressively results in nonalcoholic steatohepatitis (NASH) and eventually cirrhosis and liver cancer. Liver-specific deletion of INSIG1 promotes SREBP1 nuclear translocation to activate downstream lipogenic genes expression, leading to lipid accumulation. However, the underlying pathogenesis of NAFLD, and particularly involved in miRNA participation are still to be thoroughly explored. Here, we found that miR-363-3p was significantly overexpressed in high-fat, high-cholesterol (HFHC) diet mice liver tissue and fatty acid-induced steatosis cells. miR-363-3p directly targets INSIG1 to inhibit its expression, thereby facilitating the cleavage of SREBP and nuclear translocation to activate subsequent transcription of lipogenic genes in vitro and in vivo. In addition, we identified apigenin, a natural flavonoid compound, inhibited miR-363-3p expression to up-regulate INSIG1 and suppress nuclear translocation of SREBP1, thereby down-regulated lipogenic genes expression in steatosis cells and HFHC diet mice liver tissues. Taken together, our results demonstrated that miR-363-3p as a key regulator of hepatic lipid homeostasis targeted INSIG1, and apigenin alleviated NAFLD through the miR-363-3p/INSIG1/SREBP1 pathway. This indicates that reduction of miR-363-3p levels as a possible treatment of hepatic steatosis and provides a potential new therapeutic strategy for targeting miRNA to ameliorate NAFLD.

An integrated bioinformatics analysis to identify the shared biomarkers in patients with obstructive sleep apnea syndrome and nonalcoholic fatty liver disease.

Obstructive sleep apnea (OSA) syndrome and nonalcoholic fatty liver disease (NAFLD) have been shown to have a close association in previous studies, but their pathogeneses are unclear. This study explores the molecular mechanisms associated with the pathogenesis of OSA and NAFLD and identifies key predictive genes. Using the Gene Expression Omnibus (GEO) database, we obtained gene expression profiles GSE38792 for OSA and GSE89632 for NAFLD and related clinical characteristics. Mitochondrial unfolded protein response-related genes (UPRmtRGs) were acquired by collating and collecting UPRmtRGs from the GeneCards database and relevant literature from PubMed. The differentially expressed genes (DEGs) associated with OSA and NAFLD were identified using differential expression analysis. Gene Set Enrichment Analysis (GSEA) was conducted for signaling pathway enrichment analysis of related disease genes. Based on the STRING database, protein-protein interaction (PPI) analysis was performed on differentially co-expressed genes (Co-DEGs), and the Cytoscape software (version 3.9.1) was used to visualize the PPI network model. In addition, the GeneMANIA website was used to predict and construct the functional similar genes of the selected Co-DEGs. Key predictor genes were analyzed using the receiver operating characteristic (ROC) curve. The intersection of differentially expressed genes shared between OSA and NAFLD-related gene expression profiles with UPRmtRGs yielded four Co-DEGs: ASS1, HDAC2, SIRT3, and VEGFA. GSEA obtained the relevant enrichment signaling pathways for OSA and NAFLD. PPI network results showed that all four Co-DEGs interacted (except for ASS1 and HDAC2). Ultimately, key predictor genes were selected in the ROC curve, including HDAC2 (OSA: AUC = 0.812; NAFLD: AUC = 0.729), SIRT3 (OSA: AUC = 0.775; NAFLD: AUC = 0.750), and VEGFA (OSA: AUC = 0.812; NAFLD: AUC = 0.861) (they have a high degree of accuracy in predicting whether a subject will develop two diseases). In this study, four co-expression differential genes for OSA and NAFLD were obtained, and they can predict the occurrence of both diseases. Transcriptional mechanisms involved in OSA and NAFLD interactions may be better understood by exploring these key genes. Simultaneously, this study provides potential diagnostic and therapeutic markers for patients with OSA and NAFLD.

Paricalcitol attenuates oxidative stress and inflammatory response in the liver of NAFLD rats by regulating FOXO3a and NFκB acetylation

The lack of therapeutics along with complex pathophysiology made non-alcoholic fatty liver disease (NAFLD) a research hotspot. Studies showed that the deficiency of Vitamin D plays a vital role in NAFLD pathogenesis. While several research studies focused on vitamin D supplementation in NAFLD, there is still a need to understand the regulatory mechanism of direct vitamin D receptor activation in NAFLD. In the present study, we explored the role of direct Vitamin D receptor activation using paricalcitol in choline-deficient high-fat diet-induced NAFLD rat liver and its modulation on protein acetylation. Our results showed that paricalcitol administration significantly reduced the fat accumulation in HepG2 cells and the liver of NAFLD rats. Paricalcitol attenuated the elevated serum level of alanine transaminase, aspartate transaminase, insulin, low-density lipoprotein, triglyceride, and increased high-density lipoprotein in NAFLD rats. Paricalcitol significantly decreased the increased total protein acetylation by enhancing the SIRT1 and SIRT3 expression in NAFLD liver. Further, the study revealed that paricalcitol reduced the acetylation of NFκB and FOXO3a in NAFLD liver along with a decrease in the mRNA expression of IL1β, NFκB, TNFα, and increased catalase and MnSOD. Moreover, total antioxidant activity, glutathione, and catalase were also elevated, whereas lipid peroxidation, myeloperoxidase, and reactive oxygen species levels were significantly decreased in the liver of NAFLD after paricalcitol administration. The study concludes that the downregulation of SIRT1 and SIRT3 in NAFLD liver was associated with an increased acetylated NFκB and FOXO3a. Paricalcitol effectively reversed hepatic inflammation and oxidative stress in NAFLD rats through transcriptional regulation of NFκB and FOXO3a, respectively, by inhibiting their acetylation.

The role and mechanism of pyroptosis and potential therapeutic targets in non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome characterized by the excessive accumulation of fat within liver cells, which can progress to end-stage liver disease in severe cases, posing a threat to life. Pyroptosis is a distinct, pro-inflammatory form of cell death, differing from traditional apoptosis. In recent years, there has been growing research interest in the association between pyroptosis and NAFLD, encompassing the mechanisms and functions of pyroptosis in the progression of NAFLD, as well as potential therapeutic targets. Controlled pyroptosis can activate immune cells, eliciting host immune responses to shield the body from harm. However, undue activation of pyroptosis may worsen inflammatory responses, induce cellular or tissue damage, disrupt immune responses, and potentially impact liver function. This review elucidates the involvement of pyroptosis and key molecular players, including NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome, gasdermin D (GSDMD), and the caspase family, in the pathogenesis and progression of NAFLD. It emphasizes the promising prospects of targeting pyroptosis as a therapeutic approach for NAFLD and offers valuable insights into future directions in the field of NAFLD treatment.

Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Discovery of genomic loci for liver health and steatosis reveals overlap with glutathione redox genetics

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in the United States, encompassing a wide spectrum of liver pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite its high prevalence, there are no medications currently approved by the Food and Drug Administration for the treatment of NAFLD. Recent work has suggested that NAFLD has a strong genetic component and identifying causative genes will improve our understanding of the molecular mechanisms contributing to NAFLD and yield targets for future therapeutic investigations. Oxidative stress is known to play an important role in NAFLD pathogenesis, yet the underlying mechanisms accounting for disturbances in redox status are not entirely understood. To better understand the relationship between the glutathione redox system and signs of NAFLD in a genetically-diverse population, we measured liver weight, serum biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and graded liver pathology in a large cohort of Diversity Outbred mice. We compared hepatic endpoints to those of the glutathione redox system previously measured in the livers and kidneys of the same mice, and we screened for statistical and genetic associations using the R/qtl2 software. We discovered several novel genetic loci associated with markers of liver health, including loci that were associated with both liver steatosis and glutathione redox status. Candidate genes within each locus point to possible new mechanisms underlying the complex relationship between NAFLD and the glutathione redox system, which could have translational implications for future studies targeting NAFLD pathology.

Downregulation of Setdb2 promotes alternative activation of macrophages via the PI3K/Akt pathway to attenuate NAFLD after sleeve gastrectomy

Non-alcoholic fatty liver disease (NAFLD) stands as the most prevalent hepatic disorder, with bariatric surgery emerging as the most effective intervention for NAFLD remission. Sleeve gastrectomy (SG) has notably ascended as the predominant procedure due to its comparative simplicity and consistent surgical outcomes. Nonetheless, the underlying mechanisms remain unclear. In this study, we probed the therapeutic potential of SG for NAFLD induced by a high-fat diet (HFD) in mice, with a focus on its impact on liver lipid accumulation, macrophage polarization, and the role of the histone methyltransferase Setdb2. SG prompted significant weight loss, diminished liver size and liver-to-body weight ratio, and enhanced liver function, evidenced by reduced serum levels of triglycerides (TG), total cholesterol (T-CHO), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological examination confirmed a reduction in liver lipid accumulation. Additionally, flow cytometry unveiled an increased proportion of M2 macrophages and a decrease in Setdb2 expression was shown in the SG group, suggesting an association between Setdb2 levels and postsurgical macrophage polarization. Furthermore, the conditional knockout of Setdb2 in mice further mitigated HFD-induced steatosis and promoted the M2 macrophage phenotype. Mechanistically, Setdb2 knockout in bone marrow-derived macrophages (BMDMs) favored M2 polarization, with RNA sequencing and western blotting analyses corroborating the upregulation of the PI3K/Akt signaling pathway. The effects of Setdb2 on macrophage activation were nullified by the PI3K inhibitor LY294002, suggesting that Setdb2 facilitates alternative macrophage activation through the PI3K/Akt signaling pathway. These comprehensive findings underscore the potential of SG as a therapeutic intervention for NAFLD by regulating the critical function of Setdb2 in macrophage polarization and activation, thereby offering novel insights into NAFLD pathogenesis and therapeutic targets.

Polydatin: a potential NAFLD therapeutic drug that regulates mitochondrial autophagy through SIRT3-FOXO3-BNIP3 and PINK1-PRKN mechanisms - a network pharmacology and experimental investigation

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder that is linked to metabolic syndrome, mitochondrial dysfunction and impaired autophagy. Polydatin (PD), a natural polyphenol from Polygonum cuspidatum, exhibits various pharmacological effects and protects against NAFLD. The aim of this study was to reveal the molecular mechanisms and therapeutic potential of PD for NAFLD, with a focus on the role of mitochondrial autophagy mediated by sirtuin 3 (SIRT3), fork-head box O3 (FOXO3) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), and by PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN). We combined network pharmacology analysis, animal models and cell culture experiments to show that PD could regulate the mitochondrial autophagy pathway by modulating several key genes related to mitochondrial function, and ameliorate the liver function, histopathology and mitochondrial biogenesis of NAFLD mice and hepatocytes by activating the SIRT3-FOXO3-BNIP3 axis and the PINK1-PRKN-dependent mechanism of mitochondrial autophagy. We also identified the core targets of PD, including SIRT3, FOXO3A, CASP3, PARKIN, EGFR, STAT3, MMP9 and PINK, and confirmed that silencing SIRT3 could significantly attenuate the beneficial effect of PD. This study provided novel theoretical and experimental support for PD as a promising candidate for NAFLD treatment, and also suggested new avenues and methods for investigating the role of mitochondrial autophagy in the pathogenesis and intervention of NAFLD.

Regulating bile acids signaling for NAFLD: molecular insights and novel therapeutic interventions.

Nonalcoholic fatty liver disease (NAFLD) emerges as the most predominant cause of liver disease, tightly linked to metabolic dysfunction. Bile acids (BAs), initially synthesized from cholesterol in the liver, undergo further metabolism by gut bacteria. Increasingly acknowledged as critical modulators of metabolic processes, BAs have been implicated as important signaling molecules. In this review, we will focus on the mechanism of BAs signaling involved in glucose homeostasis, lipid metabolism, energy expenditure, and immune regulation and summarize their roles in the pathogenesis of NAFLD. Furthermore, gut microbiota dysbiosis plays a key role in the development of NAFLD, and the interactions between BAs and intestinal microbiota is elucidated. In addition, we also discuss potential therapeutic strategies for NAFLD, including drugs targeting BA receptors, modulation of intestinal microbiota, and metabolic surgery.

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

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.