Identification of Senkyunolide I as a novel modulator of hepatic steatosis and PPARα signaling in zebrafish and hamster models.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE: To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS: The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS: In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS: We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.

Visceral Fat and Diabetes: Associations With Liver Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is increasing globally. Noninvasive methods, such as bioelectrical impedance analysis (BIA), which measures body composition, including visceral fat, are gaining interest in evaluating MASLD patients. Our study aimed to identify factors associated with significant liver fibrosis, compare noninvasive scores, and highlight the importance of visceral fat measurement using BIA. Methods: MASLD patients seen in our out-patient department underwent comprehensive evaluations, including liver stiffness using transient elastography, body composition analysis using BIA, and metabolic measurements. Significant fibrosis was defined as a liver stiffness measurement of ≥8.2 kPa. Using multivariate analysis, we identified factors associated with significant liver fibrosis and compared four noninvasive scores with a novel diabetes-visceral fat 15 (DVF15) score. Results: We analyzed data from 609 MASLD patients seen between February 2022 and March 2023. The median age was 43 years (81% male). Among these, 78 (13%) had significant fibrosis. Patients with significant fibrosis had higher rates of type 2 diabetes (41% vs 21%, P < 0.001) and elevated levels of aspartate aminotransferase, alanine aminotransferase, hemoglobin A1c, Fibosis-4, aspartate-aminotransferase-to platelet-ratio index, and NAFLD fibrosis scores. They also exhibited higher visceral and subcutaneous fat. Binary logistic regression revealed type 2 diabetes and a visceral fat level of >15% as associated with significant liver fibrosis. Additionally, the DVF15 score, combining these factors, showed a modest area under the receiver operating characteristic curve of 0.664 (P < 0.001). Conclusion: Our study identified diabetes and high visceral fat as factors associated with significant liver fibrosis in MASLD patients. We recommend that visceral fat measurement using BIA be an essential part of MASLD evaluation. The presence of either diabetes or a visceral fat level of >15% should prompt clinicians to check for significant fibrosis in MASLD patients. Further research is warranted to validate our findings and evaluate the utility of the DVF15 score in larger cohorts and diverse populations.

Metabolic dysfunction-associated steatotic liver disease: A pathophysiology and clinical framework to face the present and the future.

AIMS: This review aims to provide a straightforward conceptual framework for the knowledge and understanding of Metabolic dysfunction-associated steatotic liver disease (MASLD) in the broad spectrum of steatotic liver disease and to point out the need to consider metabolic dysfunction and comorbidities as interrelated factors for a holistic approach to fatty liver disease. DATA SYNTHESIS: MASLD is the new proposed term for steatotic liver disease that replaces the old terminology of non-alcoholic fatty liver disease. This term focused on the relationship between metabolic alteration and hepatic steatosis, reflecting a growing comprehension of the association between metabolic dysfunction and hepatic steatosis. Numerous factors and conditions contribute to the underlying mechanisms, including central obesity, insulin resistance, adiponectin, lipid metabolism, liver function, dietary influences, the composition of intestinal microbiota, and genetic factors. The development of the condition, however, involves a more intricate network of components, such as neurotensin and Advanced Glycation End Products, highlighting the complexity of its pathogenesis. CONCLUSIONS: MASLD must be regarded as a complex clinical problem in which only a holistic approach can win through the coordination of multi-professional and multi-speciality interventions.

Glucagon-like peptide-1 receptor agonists: Exploring the mechanisms from glycemic control to treatment of multisystemic diseases.

This editorial takes a deeper look at the insights provided by Soresi and Giannitrapani, which examined the therapeutic potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for metabolic dysfunction-associated fatty liver disease. We provide supplementary insights to their research, highlighting the broader systemic implications of GLP-1RAs, synthesizing the current understanding of their mechanisms and the trajectory of research in this field. GLP-1RAs are revolutionizing the treatment of type 2 diabetes mellitus and beyond. Beyond glycemic control, GLP-1RAs demonstrate cardiovascular and renal protective effects, offering potential in managing diabetic kidney disease al-ongside renin-angiotensin-aldosterone system inhibitors. Their role in bone metabolism hints at benefits for diabetic osteoporosis, while the neuroprotective properties of GLP-1RAs show promise in Alzheimer's disease treatment by modulating neuronal insulin signaling. Additionally, they improve hormonal and metabolic profiles in polycystic ovary syndrome. This editorial highlights the multifaceted mechanisms of GLP-1RAs, emphasizing the need for ongoing research to fully realize their therapeutic potential across a range of multisystemic diseases.

Innovative mesenchymal stem cell treatments for fatty liver disease.

The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.

Mechanism of mesenchymal stem cells in liver regeneration: Insights and future directions.

Mesenchymal stem cells (MSCs) are a prevalent source for stem cell therapy and play a crucial role in modulating both innate and adaptive immune responses. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in liver cells and involves immune system activation, leading to histological changes, tissue damage, and clinical symptoms. A recent publication by Jiang et al, highlighted the potential of MSCs to mitigate in NAFLD progression by targeting various molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In this editorial, we comment on their research and discuss the efficacy of MSC therapy in treating NAFLD.

Addressing the alarming link between nonalcoholic fatty liver disease and cardiovascular mortality in men.

This editorial discusses the key findings presented in Batta and Hatwal's recent paper titled "Excess cardiovascular mortality in men with non-alcoholic fatty liver disease: A cause for concern!", which was published in the World Journal of Cardiology. Their original article highlights a notable correlation between nonalcoholic fatty liver disease (NAFLD) and increased cardiovascular mortality risk in men. The present commentary explores the implications of their findings, discussing potential mechanisms, risk factors, and the urgent need for integrated clinical approaches to mitigate the dual burden of these diseases. Emphasis should be placed on the importance of early detection, lifestyle modifications, and interdisciplinary collaboration for improving patient outcomes. This editorial aims to highlight the broad implications of NAFLD for cardiovascular health and to advocate for increased awareness and proactive management strategies within the medical community.

Exploring Shared Genetic Features and Molecular Mechanisms between Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma through Bioinformatics.

BACKGROUND: Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world, characterized by high incidence, high malignancy, and low survival rate. Currently, 1/4 of adults in the world suffer from Non-Alcoholic Fatty Liver Disease (NAFLD), with an incidence rate of 27% in Asia. METHODS: We used TCGA and GEO public database data sets to conduct weighted gene coexpression network analysis to identify relevant gene modules, defined the intersection of tumorigenesis-related modules and NASH development-related modules as shared genes, and then used single-factor Cox, LASSO, and multivariate Cox regression analysis screened out core shared genes and verified their prognostic value. We further investigated the relationship between core shared genes and immune infiltration, tumor mutational load, and drug sensitivity. Finally, RT-qPCR was used to verify its mRNA expression in different cell lines. RESULTS: We identified Karyopherin α 2 (KPNA2) as the core shared gene between NASH and HCC. Patients were divided into low-risk groups and high-risk groups based on the expression of KPNA2. The prognosis of the low-risk group was significantly better than that of the highrisk group. Furthermore, we found significant differences in tumor immune cell infiltration, somatic mutations, microsatellite instability, and drug sensitivity between different expression groups. CONCLUSION: There are very few studies on the molecular mechanism of the relationship between NAFLD and HCC. Our study demonstrates that KPNA2 is a potential therapeutic target and immune-related biomarker for patients with NAFLD and HCC.

Bioactive proteins and antioxidant peptides from Litsea cubeba fruit meal: Preparation, characterization and ameliorating function on high-fat diet-induced NAFLD through regulating lipid metabolism, oxidative stress and inflammatory response.

Non-alcoholic fatty liver disease (NAFLD) plays an increasingly significant threat to human health. In this study, the processing by-products of Litsea cubeba fruit meal were defatted by ultrasound-assisted methods, then the acetone-precipitated protein of L. cubeba (LCP) was obtained and structural analysis was performed. LCP was hydrolyzed by a two-step sequential hydrolysis method using alcalase and papain. Subsequently, antioxidant peptide fraction (IV2) was isolated and identified from the resultant hydrolysate through membrane ultrafiltration, Sephadex G-15 chromatography, and liquid chromatograph mass spectrometer (LC-MS). Animal experimentation indicated the potential of IV2 to mitigate hepatic steatosis. Moreover, IV2 could effectively reduce oxidative stress-induced damage by modulating the Keap1-Nrf2 pathway to activate downstream heme oxygenase-1 (HO-1) and NAD(P) H quinone oxidoreductase 1 (NQO1). Integrating metabolomics and transcriptomics revealed enrichment in pathways associated with glycerolipid metabolism and fatty acid ß-oxidation, suggesting the principal mechanisms underlying IV2's ameliorative effects on NAFLD. Transcriptome sequencing identified 3092 up-regulated and 3010 down-regulated genes following IV2 treatment. Interaction analyses based on different lipid compositions (DELs) and differentially expressed genes (DEGs) indicated that IV2 primarily alleviated hepatic steatosis by modulating peroxisome proliferator-activated receptor α (PPAR-α) related pathways, thereby augmenting fatty acid ß-oxidation within liver cells. These results indicate that IV2 shows potential in improving high-fat diet (HFD)-induced NAFLD, with improved fatty acid ß-oxidation and reduced triglyceride biosynthesis emerging as underlying mechanisms.

Novel insights into the role of quercetin and kaempferol from Carthamus tinctorius L. in the management of nonalcoholic fatty liver disease via NR1H4-mediated pathways.

This study investigates the novel therapeutic potential of quercetin and kaempferol, two bioactive compounds derived from Carthamus tinctorius L., in treating nonalcoholic fatty liver disease (NAFLD) by modulating the bile acid receptor NR1H4 (Nuclear Receptor Subfamily 1 Group H Member 4) and its associated metabolic pathways. A rat model of NAFLD was established, and RNA sequencing and proteomics were carefully employed to identify differential gene expressions associated with the disease. The active components of Carthamus tinctorius L. were screened, followed by the construction of a comprehensive network that maps the interactions between these components, NR1H4 and NAFLD-related pathways. Both in vitro (using HepG2 cells) and in vivo experiments were conducted to evaluate the effects on NR1H4 expression levels through Western blot and RT-qPCR analyses. Our findings identify NR1H4 as a pivotal target in NAFLD. Network pharmacology analysis indicates that quercetin and kaempferol play crucial roles in combating NAFLD, with in vitro and in vivo experiments confirming their ability to mitigate hepatocyte steatosis by enhancing NR1H4 expression. Notably, the protective effects of these compounds were inhibited by the NR1H4 antagonist guggulsterone, highlighting the importance of NR1H4 upregulation. This study demonstrates the novel therapeutic efficacy of quercetin and kaempferol from Carthamus tinctorius L. in treating NAFLD through NR1H4 upregulation. This mechanism contributes to the regulation of lipid metabolism, improvement of liver function, reduction of inflammation, and alleviation of oxidative stress, offering a promising direction for future NAFLD treatment strategies.

Decoding the Knacks of Ellagitannin Lead Compounds to Treat Nonalcoholic Fatty Liver Disease using Computer-aided Drug Designing.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, impacting individuals in Western nations and rapid growing in Asian countries due to sedentary lifestyles; thus, NAFLD has emerged as a significant worldwide health concern. Presently, lifestyle changes represent the primary approach to managing NAFLD. METHODS: This research aimed to identify the potential drug targets for treating NAFLD through comprehensive in silico computational analysis. These include the prediction of the three-dimensional structure of the protein, the prediction of inhibitors by PubChem and ZINC, molecular docking by Autodcok, pharmacophore modeling, molecular dynamics simulation by the OPLS_2005 force field, and the orthorhombic box solvent model Intermolecular Interaction Potential 3 Points Transferable to the selected compound. The toxicity of the lead compounds was analyzed through AdmetSAR software. RESULTS: The protein associated with the PNPLA3 gene, whose overall three-dimensional structure was 95% accurate, were retrieved following inhibitor selection via PubChem and ZINC. Among the selected inhibitors and docked compounds with ID 10033935 (ellagitannin) showed a minimum E-Score of -17.266. In docking and pharmacophore modeling the compound ellagitannin shows promise as a potential drug candidate. Moreover, the molecular dynamics and structural stability of the protein-ligand complex were evaluated with several metrics such as as root mean square fluctuation and root mean square deviation and resulted in the stability not only of PNPLA3-10033935 (ellagitannin) but also of compound PNPLA3-71448940 and PNPLA3-5748394 complexed proteins at 400 ns with very slight variation. CONCLUSION: Overall, ellagitannin was identified as the best druggable target with the best therapeutics profile. The findings of our study can pave the way for the development of a new drug against NALFD.

Long Non-Coding RNAs in Non-Alcoholic Fatty Liver Disease; Friends or Foes?

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a range of conditions that start with the accumulation of fat in the liver (hepatic steatosis) and can progress to more severe stages like steatohepatitis (NASH) and fibrosis without drinking alcohol. Environmental and genetic variables both contribute to MAFLD's development, with various biological processes and mediators involved at every phase. Long non-coding RNAs (lncRNAs) are a class of RNA molecules that are not translated into protein and are over 200 nucleotides long. They can impact genes that encode protein by controlling transcriptional and post-transcriptional procedures. Dysregulation of lncRNA has been connected to several liver diseases, including MAFLD. Recent research has linked lncRNAs to MAFLD pathology in both patients and animal models. However, the roles of most lncRNAs in MAFLD pathology are still not well recognized. This review provides a comprehensive catalog of recently reported lncRNAs in the pathogenesis of MAFLD and summarizes the current knowledge of lncRNAs usage as therapeutic strategies in MAFLD, the most common liver disease. Collectively, lncRNA's targeting could potentially offer a therapeutic approach by modulating MAFLD.

Efficacy of the Mediterranean diet in treating metabolic dysfunction-associated steatotic liver disease (MASLD) in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: There are limited treatment options for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic Fatty Liver Disease (MASLD) in children and adolescents. AIM: To evaluate the effectiveness of the Mediterranean diet in improving liver function in children and adolescents with MASLD. METHODS: In this systematic review and meta-analysis, we searched PubMed, Scopus, Embase, CINAHL, and Cochrane CENTRAL for interventional studies investigating the effect of Mediterranean diet on MASLD in children and adolescents. The primary outcome was a change in liver function measured using these liver enzymes; Alanine Transaminase (ALT), Aspartate Transaminase (AST) and Gamma-glutamyl transferase (GGT). The secondary outcomes were lipid profile, body weight, and insulin resistance. The risk of bias was assessed using the MASTER scale. Bias-adjusted inverse variance heterogeneity models were used to synthesize overall weighted mean differences for the treatment effect (WMD) and their 95% confidence intervals. Heterogeneity and publication bias were evaluated using the I2 statistics, Tau-squared and Doi plots, respectively. RESULT: Out of 5915 study records identified from database searches, five studies with 308 participants, two randomized controlled trials, and three quasi-experimental studies, met the inclusion criteria. In overall synthesis, the Mediterranean diet was associated with moderate improvements in liver function as shown by reductions in the liver enzymes [ALT - WMD - 10.85 U/L, 95% CI -20.03 to -1.68, I2 = 42, T2 = 38.8, AST - WMD - 9.26 U/L, 95% CI -17.14 to -1.38, I2 = 70.7, T2 = 42.7, and GGT - WMD - 1.99 95% CI -5.09 to 1.11)], but changes in body weight, lipid profile and insulin resistance were small and insignificant. CONCLUSION: The Mediterranean diet may improve liver function in children with MASLD. More randomized controlled trials are needed to develop high-certainty evidence on these findings. REGISTRATION: This protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) CRD42023426939. 31/05/2023.

Prevalence of Clinically Significant Liver Fibrosis as Measured by Transient Elastography due to Non-alcoholic Fatty Liver Disease in Indian Individuals with Type 2 Diabetes Mellitus.

Introduction: There is high prevalence of non-alcoholic fatty liver disease in individuals with type 2 diabetes mellitus (T2D), and available evidence suggests higher prevalence of NASH and advanced stages of fibrosis among T2D. Data regarding prevalence of clinically significant liver fibrosis (CSLF) in individuals with T2D is scarce. We investigated the prevalence of transient elastography (TE)-proven CSLF among patients of T2D attending a diabetes clinic at a tertiary care center. Methods: A cross-sectional descriptive evaluation study of 603 consecutive adults with T2D was conducted to detect CSLF using TE. Steatosis was diagnosed using a controlled attenuation parameter >237 dB/m. Results: The prevalence of CSLF was 22.7%, and the prevalence of steatosis was 58.9% in our study. A higher body mass index (BMI) (P = 0.001), aspartate aminotransferase (AST; P = 0.0001), alanine aminotransferase (ALT; P = 0.0001), and low platelets (P = 0.0001) were independent factors associated with CSLF. Elevated ALT and AST (≥40 units/L) levels were present in only 27.7% and 37.2% of individuals with CSLF, respectively. Twenty-six (4.31%) individuals had LSM > 13.0 kPa. Conclusion: CSLF is highly prevalent in T2D patients attending a diabetes clinic at a tertiary care center, and the majority of such individuals have normal transaminase levels. Higher BMI, AST, and ALT values and lower platelet counts are associated with liver fibrosis.

Understanding Insulin Resistance in NAFLD: A Systematic Review and Meta-Analysis Focused on HOMA-IR in South Asians.

Non-alcoholic fatty liver disease (NAFLD), a metabolic condition, is becoming increasingly common in South Asia. While its clinical diagnosis primarily relies on sonography and altered hepatic biomarkers, the significance of non-hepatic indicators, such as Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), in relation to NAFLD requires further examination in the South Asian population due to ethnic differences in these markers. This study examined the relationship between insulin resistance, quantified using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and NAFLD, along with other non-hepatic biomarkers. A thorough literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed, Embase, and Google Scholar databases, yielding 287 articles. After applying the selection criteria and screening, 22 studies were selected for inclusion in the analysis. We extracted and meta-analyzed the data on HOMA-IR in patients with NAFLD, along with other relevant parameters. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of observational studies, whereas the RoB 2.0 tool was employed for randomized controlled trials (RCTs). The systematic review uncovered that individuals with NAFLD demonstrated statistically significant elevations in HOMA-IR levels, with a weighted mean difference (WMD) of 1.28 (95% confidence interval (CI): 1.00-1.58, I² = 98%, p < 0.0001) when compared to healthy subjects. Additionally, NAFLD patients showed markedly higher fasting blood glucose (FBG) levels, with a combined mean difference of 15.64 mg/dL (95% CI: 11.03-20.25, I² = 92%, p < 0.0001). The analysis also revealed increased triglyceride levels in NAFLD patients, with a pooled mean difference of 42.49 mg/dL (95% CI: 29.07-55.91, I² = 97%, p < 0.0001), and elevated C-reactive protein (CRP) levels, with a pooled mean difference of 2.17 mg/L (95% CI: 2.01-2.33, I² = 23%, p < 0.0001). Interestingly, subgroup analysis indicated that obese NAFLD patients exhibited significantly higher HOMA-IR levels than their non-obese counterparts, with a weighted mean difference of 5.85 (95% CI: 4.88-6.81, I² = 0%, p < 0.0001). Variations in study methodology, diagnostic techniques, and subject demographics were identified as sources of heterogeneity. The analysis found little evidence of publication bias, which lends credibility to the results. In South Asian populations, higher HOMA-IR, triglyceride-glucose (TyG) index, and CRP levels are associated with an increased risk of NAFLD. To improve the understanding and treatment of NAFLD in this specific demographic group, it is necessary to establish uniform diagnostic criteria and conduct additional studies, particularly RCTs.

D-Xylose Ameliorates Non-Alcoholic Fatty Liver Disease by Targeting Macrophage-expressed LYZ Gene.

This study investigates the therapeutic effects of D-Xylose, a natural sugar, on non-alcoholic fatty liver disease (NAFLD), focusing on the expression of the lysozyme gene (LYZ) in macrophages. Using the single-cell dataset GSE136103 for NAFLD, researchers analyzed macrophage populations and other groups utilizing the Seurat package in R, while a differential analysis was performed on the NAFLD dataset GSE61260 using the limma package. Both in vitro and in vivo models, including cell culture, mouse models, RT-qPCR, Western blot, ELISA, and histopathological analyses, were employed to examine the effect of D-Xylose on lipid accumulation, LYZ expression, blood lipid levels, and inflammatory responses. The study found a significant upregulation of LYZ in free fatty acid (FFA)-treated cells and mouse liver tissues, with a subsequent reduction after D-Xylose intervention. Treatment with D-Xylose and Amlodipine led to a notable decrease in lipid accumulation, as evidenced by reduced triglyceride and cholesterol levels. D-Xylose demonstrated a greater improvement in lipid metabolism than Amlodipine. Additionally, D-Xylose significantly mitigated inflammatory responses, reducing levels of inflammatory markers such as IL1R, IL6, MYS8, TNF, NF-κB, and IL-1. Furthermore, D-Xylose administration significantly reduced liver weight and liver index, with a positive impact on serum liver function and blood lipid levels. The findings suggest that D-Xylose could be a therapeutic intervention for NAFLD by targeting LYZ expression in macrophages, thereby modulating lipid metabolism and inflammatory responses.

Multi-omics joint analysis reveals that the Miao medicine Yindanxinnaotong formula attenuates non-alcoholic fatty liver disease.

BACKGROUD: Non-alcoholic fatty liver disease (NAFLD) is a growing chronic liver disease worldwide, and no effective agent is approved yet for this condition. Traditional Chinese Medicine (TCM), which has been practiced for thousands of years in China and other Asian countries, is considered an important source for identifying novel medicines for various diseases. Miao medicine Yindanxinnaotong formula (YDX) is a classical TCM for the treatment of hyperlipidemia disease by reducing blood lipid content, while the role of YDX have not been clarified in NAFLD. PURPOSE: To investigate the protective effect of YDX on NAFLD in mice induced by high fat diet (HFD) and clarify the potential mechanism. METHODS: NAFLD mice model was constructed by receiving HFD for 10-week period with or without YDX administration. Lipid profiles, biochemical indicators, and histopathological staining were performed to evaluate the extent of hepatic lipid accumulation and hepatic steatosis. 16S rRNA sequencing was used to determine the gut microbial composition. Serum metabolomics was further used to investigate the changes in plasma biomarkers for NAFLD-associated by UPLC-Q-TOF/MS analysis. Subsequently, liver transcriptomics was employed to identify differentially expressed genes and explore regulatory pathways. Then, lipid metabolism-related proteins and inflammation factors were examined by Western blot and ELISA. RESULTS: YDX reduced body weight gain, liver index and inflammatory cytokines levels, along with improved hepatic steatosis, serum lipid profile, sensitivity to insulin and also tolerance to glucose, and enhanced oxidative defense system in HFD-induced mice. Also, YDX remarkedly affected gut microbiota diversity and community richness and decreased the ratio of Firmicutes/Bacteroidetes. Meanwhile, YDX also reduced the production of harmful lipid metabolites in the sera of NAFLD mice, such as LPC(18:0), LPC(18:1) and carnitine. Notably, consistent with liver transcriptomics results, YDX downregulated the expression of proteins implicated in de novo lipid synthesis (Srebp-1c, Acaca, Fasn, Scd-1, and Cd36) and pro-inflammatory cytokines (IL-6 and TNF-α), and increased the expression of proteins-related fatty acid ß-oxidation (Ampkα, Ppar-α, and Cpt-1) in the liver by activating Ampk pathway. CONCLUSION: YDX is promisingly an effective therapy for preventing NAFLD by modulating the Ampk pathway, inhibiting gut microbiota disorder, and reducing the production of harmful lipid metabolites.

Comparative effectiveness of five Chinese patent medicines for non-alcoholic fatty liver disease: A systematic review and Bayesian network meta-analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a metabolically stressed liver injury closely related to insulin resistance and genetic susceptibility and has become the leading chronic liver disease in China. PURPOSE: To analyze the effectiveness of five Chinese patent medicines used alone or in combination with western medications (WM) for NAFLD using Bayesian network meta-analysis. METHODS: Searches were conducted in Embase, Cochrane Library, PubMed, CNKI, Wanfang Database, VIP, and SinoMed for randomized controlled trials (RCTs) on Danning tablets, Huazhi Rougan granules, Dangfei Liganning capsules, Kezhi capsules, and Qianggan capsules, either alone or in combination with WM for NAFLD, up to January 10, 2024. This study was screened based on pre-designed inclusion and exclusion criteria, and the risk of bias was evaluated using the Cochrane ROB2 tool. The primary outcome was clinical efficacy rate, while secondary outcomes included levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Triglycerides (TG), and Low-density lipoprotein cholesterol (LDL-C). These data will be analyzed using WinBUGS 1.4.3 and then visualized using Stata 14.0 software. RESULTS: A total of 77 RCTs involving 7770 patients were included. The results indicated that Huazhi Rougan granules combined with WM (OR = 0.13, 95 % CI 0.05 ∼ 0.26) had a SUCRA probability value of 81.7 %, ranked first in clinical efficacy and significantly improved blood lipids levels including TG, High-density Lipoprotein Cholesterol (HDL-C), and LDL-C, Total cholesterol (TC). For the Chinese patent medicines alone, Danning tablets led with a 75.3 % clinical efficacy rate. Huazhi Rougan granules significantly increased levels of ALT (96.2 %) and AST (MD = -14.48, 95 % CI -23.38 ∼ -5.32). Dangfei Liganning capsules demonstrated significant efficacy in improving TG (73.1 %) and TC (83 %) levels. CONCLUSION: In the treatment of NAFLD, the combination of Huazhi Rougan granules and WM demonstrated significant clinical effectiveness and improvement in blood lipid profiles. For different outcome indicators, Danning tablets used alone showed the highest clinical efficacy, while significant improvement in liver function indicators was best achieved with Huazhi Rugan granules used alone.

Lipidomics reveals the lipid-lowering and hepatoprotective effects of Celosia Semen on high-fat diet-induced NAFLD mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Celosia Semen (CS) serves as a traditional Chinese medicine (TCM) for promoting liver health and enhancing vision, with extensive clinical applications. Triterpenoid saponins represent the primary active components of CS, with the highest concentration of Celosin I (CI) detected. The urgent need for effective NAFLD treatments motivated us assess the beneficial effects of total saponins from CS (TSCS) and CI. AIMS OF THE STUDY: To investigate the therapeutic effects of TSCS and CI on NAFLD and its underlying molecular mechanisms. MATERIALS AND METHODS: The impact of TSCS and CI on NAFLD was evaluated through in vitro and in vivo methodologies, utilizing high-fat diet (HFD) and palmitic acid/oleic acid modeling on C57BL/6J mice and AML12 cells, respectively. Biochemical analysis, H&E and Oil red O staining were used to characterize the lipid-lowering and hepatoprotective activities of TSCS and CI. Lipidomics discerned the impact of TSCS and CI interventions on liver lipid composition, distribution and alteration in NFALD mice. RT-qPCR and western blotting detected the influence of TSCS and CI on genes linked to de novo lipogenesis, fat calculation uptake, oxidation and esterification. The docking analysis anticipated the interaction of six major triterpenoid saponins within TSCS with SREBP1. RESULTS: TSCS and CI markedly diminished lipid accumulation induced by high fat both in vivo and in vitro. TSCS and CI also mitigated hepatic steatosis and liver injury induced by HFD through the reduction of TC, TG, FAs, ALT, and AST, even at minimal dose of 25 mg/kg. Lipidomics indicated that TSCS and CI had the potential to modulate the lipid metabolism network, rectify lipid metabolic dysregulation induced by NAFLD, decrease the levels of harmful lipids, and elevate the levels of advantageous lipids. Furthermore, TSCS and CI exhibited a strong affinity to SREBP1, thereby might directly influence the expression of SREBP1 and a cascade of essential enzymes involved in de novo lipogenesis, and finally resulting in a diminished synthesis of novel lipids. CONCLUSION: TSCS and CI were confirmed firstly as key active components of CS in amending hepatic steatosis and mitigate liver damage in NAFLD, outlining the preliminary mechanism. They warrant further exploration as drug candidates for NAFLD treatment, especially in light of the current shortage of medications and limited therapeutic options.

Body Composition and Progression of Biopsy-Proven Non-Alcoholic Fatty Liver Disease in Patients With Obesity.

BACKGROUND: Obesity is a significant risk factor for the progression of non-alcoholic fatty liver disease (NAFLD). However, a convenient and efficacious non-invasive test for monitoring NAFLD progression in patients with obesity is currently lacking. This study aims to investigate the associations between CT-based body composition and the progression of biopsy-proven NAFLD in patients with obesity. METHODS: Liver biopsy was conducted in patients with obesity, and the progression of NAFLD was evaluated by the NAFLD activity score (NAS). Body composition was assessed through abdominal computed tomography (CT) scans. RESULTS: A total of 602 patients with an average age of 31.65 (±9.33) years old were included, comprising 217 male patients and 385 female patients. The wall skeletal muscle index (SMI), total SMI, and visceral fat index (VFI) were positively correlated with NAS in both male and female patients. Multivariate regression analysis demonstrated significant associations between high liver steatosis and wall SMI (HR: 1.60, 95% CI: 1.12 to 2.30), total SMI (HR: 1.50, 95% CI: 1.02 to 2.08), VSI (HR: 2.16, 95% CI: 1.48 to 3.14), visceral fat to muscle ratio (HR: 1.51, 95% CI: 1.05 to 2.18), and visceral to subcutaneous fat ratio (HR: 1.51, 95% CI: 1.07 to 2.12). Non-alcoholic steatohepatitis (NASH) was significantly associated with wall SMI (HR: 1.52, 95% CI: 1.06 to 2.19) and VSI (HR: 1.50, 95% CI: 1.03 to 2.17). Liver fibrosis ≥ F2 was significantly associated with psoas muscle index (HR: 0.64, 95% CI: 0.44 to 0.93) and psoas skeletal muscle density (HR: 0.61, 95% CI: 0.41 to 0.89). CONCLUSIONS: Our study suggested that certain CT-based body composition indicators, notably high VFI, were significantly associated with the progression of NAFLD in patients with obesity. Great attentions and timely managements should be given to these patients with body composition characteristics associated with the risk of NAFLD progression.