Vinpocetine and Lactobacillus improve fatty liver in rats: role of adiponectin and gut microbiome.

Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates for hepatic inflammation like that occurring in non-alcoholic fatty liver disease (NAFLD). In the current study, we examined the therapeutic impact of the phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results show that Vinpo (10 and 20 mg/kg/day) dose-dependently curbed HFD-induced elevation of liver injury parameters in serum (ALT, AST) and tissue histopathology. These effects were concordant with Vinpo's potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-ß1) and oxidative stress (MDA, NOx) alongside restoring the antioxidant-related parameters (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like high mobility group box (HMGB)1 alongside lowering the overactivation of the pattern recognition receptors including, toll-like receptor (TLR)4 and receptor for advanced glycation end-products (RAGE). Consequently, there was less activation of the transcription factor nuclear factor-kappa B that lowered production of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes rats. Compared to Vinpo treatment alone, Lactobacillus probiotics as adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting NAFLD in humans.

Multi-dimensional comparison of abdominal obesity indices and insulin resistance indicators for assessing NAFLD.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD. METHODS: A retrospective large-scale, population-based study was conducted based on the data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test. RESULTS: In total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices. CONCLUSIONS: All six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices.

Objective measures of cardiometabolic risk and advanced fibrosis risk progression in primary care patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: We examined the association of objective measures of cardiometabolic risk with progression to a high-risk for advanced fibrosis in patients with MASLD at initially low- and indeterminate-risk for advanced fibrosis. METHODS: We performed a retrospective cohort study of primary care patients with MASLD between 2012 and 2021. We evaluated patients with MASLD and low- or indeterminate-risk Fibrosis-4 Index (FIB-4) scores and followed them until the outcome of a high-risk FIB-4 (>2.67), or the end of the study period. Exposures of interest were body mass index (BMI), systolic blood pressure (SBP), hemoglobin A1c, cholesterol, estimated glomerular filtration rate (eGFR), and smoking status. Variables were categorized by the threshold for primary care therapy intensification. Unadjusted and adjusted Cox regression models were developed for the outcome of time to a high-risk FIB-4 value. RESULTS: The cohort included 1,347 patients with a mean follow-up of 3.6 years (SD 2.7). Of the cohort, 258 (19%) had a subsequent FIB-4 > 2.67. In the fully adjusted Cox regression models, mean SBP > 150 mm Hg (1.57; 95%CI 1.02-2.41) and eGFR < 59 ml/min (HR 2.78; 95%CI 2.17-3.58) were associated with an increased hazard of a high-risk FIB-4, while receiving a statin prescription (HR 0.51; 95%CI 0.39-0.66) was associated with a lower risk. CONCLUSIONS: Nearly 1 in 5 primary care patients with MASLD transitioned to a high-risk FIB-4 score during 3.6 years of follow-up, and uncontrolled blood pressure and reduced kidney function were associated with an increased hazard of a FIB-4 at high-risk for advanced fibrosis.

Prevalence and Characteristics of Metabolic Dysfunction-Associated Fatty Liver Disease among an Iranian Adult Population with Ethnic and Genetic Diversity: Results of the PolyIran-Liver Study.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a rising global public health concern. It has been demonstrated that its prevalence and characteristics vary by region and racial/ethnicity. We aimed to investigate the prevalence of MAFLD and its characteristics among Turkmen and non-Turkmen ethnic groups in a multiethnic population region of Iran. Methods: In this cross-sectional study, we analyzed baseline data for 1614 participants, aged above 50 years, from the PolyIran-Liver trial who were randomly selected from Gonabad city and determined the prevalence of MAFLD and its demographic and metabolic disorders for both the Turkmen and non-Turkmen ethnic groups. Multivariate binary logistic regressions were applied to identify MAFLD-associated factors for men and women separately for the Turkmen and non-Turkmen populations. Results: The mean (SD) age of the participants was 59.1(6.7) years. Of the participants, 51.5% (n=831) were men, and 52.9% (n=854) were Turkmen. The prevalence of MAFLD among the overall study population was 39.8% (n=614). It was more common among women (45.8% vs. 34.1% in men, P<0.001), non-Turkmens (43.9% vs. 36.1% in Turkmens, P<0.001), and at age 50-64 (41.5% vs.36.1% in age≥65 P=0.004). The fully adjusted multivariate analysis in sex strata exhibited an independent negative association between Turkmen ethnicity only among men but not among women. The increased waist circumference (WC) was the most common metabolic disorder, observed in more than 95.5% of patients with MAFLD (P<0.001). Multivariate analysis in sex/ethnic strata with adjustment for potential confounders revealed an independent association of MAFLD with increased WC, insulin resistance, impaired fasting glucose/diabetes type 2, and high alanine aminotransferase (ALT) among women in both ethnic groups while with elevated triglyceride (TG) only among Turkmen and high body mass index (BMI) only among non-Turkmen women. Increased WC had the strongest independent association with MAFLD among women and the highest odds ratio (OR) with MAFLD in Turkmen women (OR: 6.10; 95% CI 1.56-23.86 vs. 4.80 in non-Turkmen women). Among men, MAFLD was independently associated with insulin resistance, high BMI, and high ALT in both ethnic groups and elevated TG only in non-Turkmen men (all P<0.001). Insulin resistance had the strongest independent OR with MAFLD among men with similar size in both ethnic groups (4.68 [95% CI 2.56-8.55]) in non-Turkmen men and 4.37 (95% CI 2.27-8.42 in Turkmen men). Conclusion: This study revealed the high prevalence of MAFLD with a sex and ethnic disparity in the middle-aged population of Gonabad city. Further research is needed to understand the factors contributing to the higher prevalence of MAFLD in this region, particularly in women. Furthermore, considering the diverse ethnic population of Iran, it is suggested that future investigations on the sex and ethnic aspects of MAFLD in the Iranian population be conducted to provide targeted prevention strategies better suited for the Iranian population.

Oral Insulin Alleviates Liver Fibrosis and Reduces Liver Steatosis in Patients With Metabolic Dysfunction-associated Steatohepatitis and Type 2 Diabetes: Results of Phase II Randomized, Placebo-controlled Feasibility Clinical Trial.

Background and Aims: Metabolic dysfunction-associated steatohepatitis is an advanced form of nonalcoholic fatty liver disease and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease. Methods: This double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of oral 8 mg insulin in patients with metabolic dysfunction-associated steatohepatitis and type 2 diabetes mellitus. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n = 21) or placebo (n = 11) capsule. Safety was monitored throughout the study. MRI-proton density fat fraction assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment. Results: No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs -6.5%, respectively) and liver segment 3 (-11.7% vs +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline hemoglobin A1c levels. Mean percent changes from baseline alanine aminotransferase, and aspartate aminotransferase levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm. Conclusion: The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744).

Comparative effects of viable Lactobacillus rhamnosus GG and its heat-inactivated paraprobiotic in the prevention of high-fat high-fructose diet-induced non-alcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver alterations worldwide, being gut microbiota dysbiosis one of the contributing factors to its development. The aim of this research is to compare the potential effects of a viable probiotic (Lactobacillus rhamnosus GG) with those exerted by its heat-inactivated paraprobiotic counterpart in a dietary rodent model of NAFLD. The probiotic administration effectively prevented the hepatic lipid accumulation induced by a high-fat high-fructose diet feeding, as demonstrated by chemical (lower TG content) and histological (lower steatosis grade and lobular inflammation) analyses. This effect was mainly mediated by the downregulation of lipid uptake (FATP2 protein expression) and upregulating liver TG release to bloodstream (MTTP activity) in rats receiving the probiotic. By contrast, the effect of the paraprobiotic preventing diet-induced liver lipid accumulation was milder, and mainly derived from the downregulation of hepatic de novo lipogenesis (SREBP-1c protein expression and FAS activity) and TG assembly (DGAT2 and AQP9 protein expression). The obtained results demonstrate that under these experimental conditions, the effects induced by the administration of viable L. rhamnosus GG preventing liver lipid accumulation in rats fed a diet rich in saturated fat and fructose differ from those induced by its heat-inactivated paraprobiotic counterpart.

Association between RC/HDL-C ratio and risk of non-alcoholic fatty liver disease in the United States.

Background: The occurrence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. The link between serum remnant cholesterol (RC) to high-density lipoprotein cholesterol (HDL-C) ratio and NAFLD remains unclear. Therefore, we sought to clarify the relationship between the RC/HDL-C ratio and the NAFLD. Methods: Data for our cross-sectional study came from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) with 2,269 participants. Associations between RC/HDL-C levels and the prevalence of NAFLD and hepatic fibrosis were evaluated using adjusted multivariate logistic regression analyses. A generalized additive model examined the non-linear relationship between RC/HDL-C and the probability of developing NAFLD. Results: Among 2,269 participants, 893 (39.36%) were diagnosed with NAFLD. In each of the three models, RC/HDL-C and NAFLD had a strong positive statistical relationship: model 1 (OR = 9.294, 95%CI: 6.785, 12.731), model 2 (OR = 7.450, 95%CI: 5.401, 10.278), and model 3 (OR = 2.734, 95%CI: 1.895, 3.944). In addition, the subgroup analysis by gender and BMI suggested that RC/HDL-C showed a positive correlation with NAFLD. The RC/HDL-C ratio was positively correlated with the degree of liver steatosis. There was an inverted U-shaped connection between the prevalence of NAFLD and RC/HDL-C, with an inflection point of 0.619 for all participants and 0.690 for men. Receiver operating characteristic (ROC) analysis showed that the predictive value of RC/HDL-C for NAFLD (area under the curve: 0.7139; 95%CI: 0.6923, 0.7354; P < 0.001), was better than traditional lipid parameters. Conclusion: Increased RC/HDL-C levels are independently associated with an increased risk of NAFLD and the severity of liver steatosis in the American population. In addition, the RC/HDL-C ratio can be used as a simple and effective non-invasive biomarker to identify individuals with a high risk of NAFLD.

Unveiling structural determinants for FXR antagonism in 1,3,4-trisubstituted-Pyrazol amide derivatives: A multi-scale in silico modelling approach.

Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern due to its potential to progress into severe liver diseases. Targeting the bile acid receptor FXR has emerged as a promising strategy for managing NAFLD. Building upon our previous research on FXR partial agonism, the present study investigates a series of 1,3,4-trisubstituted-pyrazol amide derivatives as FXR antagonists, aiming to delineate the structural features for antagonism. By means of 2D-QSAR (quantitative structure-activity relationships) modelling techniques, we elucidated the key structural elements responsible for the antagonistic properties of these derivatives. We then employed QPhAR, an open-access software, to identify key molecular features within the compounds that enhance their antagonistic activity. Additionally, 3D-QSAR modelling allowed us to analyse the steric and electrostatic fields of aligned 3D structures, further refining our understanding of structure-activity relationships. Subsequent molecular dynamics simulations provided insights into the binding mode interactions between the compounds and FXR, with varying potencies, confirming and complementing the findings from 2D-QSAR, pharmacophore, and 3D-QSAR modelling. Particularly, our study highlighted the significance of hydrophobic interactions in conferring potent antagonism by the 1,3,4-trisubstituted-pyrazol amide derivatives against FXR. Overall, this work underscores the potential of 1,3,4-trisubstituted-pyrazol amides as FXR antagonists for NAFLD treatment. Notably, our reliance on open-access software fosters reproducibility and broadens the accessibility of our findings.

Targeting histone methylation and demethylation for non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, facing increasing challenges in terms of prevention and treatment. The methylation of lysine and arginine residues on histone proteins is dynamically controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs), regulating chromatin structure and gene transcription. Mutations, genetic translocations, and altered gene expression involving HMTs and HDMs are frequently observed in NAFLD. HMTs and HDMs are receiving increasing attention in regulating NALFD. Targeting specific HMTs and HDMs for drug development is becoming a new strategy for treating NAFLD. This review provides a comprehensive summary of the regulatory mechanism of histone methylation/demethylation in NAFLD. Additionally, we discuss the potential applications of HMTs and HDMs inhibitors in preventing NAFLD, which may provide a scientific basis for the treatment of NAFLD.

NAFLD (MASLD)/NASH (MASH): Does It Bother to Label at All? A Comprehensive Narrative Review.

Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over time. While steatosis is a prominent histological characteristic and recognizable grossly and microscopically, liver biopsies of individuals with NASH/MASH may exhibit several other abnormalities, such as mononuclear inflammation in the portal and lobular regions, hepatocellular damage characterized by ballooning and programmed cell death (apoptosis), misfolded hepatocytic protein inclusions (Mallory-Denk bodies, MDBs), megamitochondria as hyaline inclusions, and fibrosis. Ballooning hepatocellular damage remains the defining feature of NASH/MASH. The fibrosis pattern is characterized by the initial expression of perisinusoidal fibrosis ("chicken wire") and fibrosis surrounding the central veins. Children may have an alternative form of progressive NAFLD/MASLD characterized by steatosis, inflammation, and fibrosis, mainly in Rappaport zone 1 of the liver acinus. To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using a score for evaluating NAFLD/MASLD in a comprehensive narrative review. The search for articles was conducted between 1 January 2000 and 31 December 2023, on the PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases. This search was complemented by a gray search, including internet browsers (e.g., Google) and textbooks. The following research question guided the study: "What are the basic data on using a score for evaluating NAFLD/MASLD?" All stages of the selection process were carried out by the single author. Of the 1783 articles found, 75 were included in the sample for analysis, which was implemented with an additional 25 articles from references and gray literature. The studies analyzed indicated the beneficial effects of scoring liver biopsies. Although similarity between alcoholic steatohepatitis (ASH) and NASH/MASH occurs, some patterns of hepatocellular damage seen in alcoholic disease of the liver do not happen in NASH/MASH, including cholestatic featuring steatohepatitis, alcoholic foamy degeneration, and sclerosing predominant hyaline necrosis. Generally, neutrophilic-rich cellular infiltrates, prominent hyaline inclusions and MDBs, cholestasis, and obvious pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced hepatocellular injury over NASH/MASH. Multiple grading and staging methods are available for implementation in investigations and clinical trials, each possessing merits and drawbacks. The systems primarily used are the Brunt, the NASH CRN (NASH Clinical Research Network), and the SAF (steatosis, activity, and fibrosis) systems. Clinical investigations have utilized several approaches to link laboratory and demographic observations with histology findings with optimal platforms for clinical trials of rapidly commercialized drugs. It is promising that machine learning procedures (artificial intelligence) may be critical for developing new platforms to evaluate the benefits of current and future drug formulations.

Current strategies for nonalcoholic fatty liver disease treatment (Review).

Nonalcoholic fatty liver disease (NAFLD), the most common chronic hepatic disease, has become a leading health problem worldwide. The present review summarized the methods and mechanisms to treat NAFLD, including the Mediterranean diet, physical activity and exercise, bariatric surgery and specific therapeutic agents, including statins, peroxisome proliferator­activated receptor agonists, cenicriviroc and farnesoid X receptor agonists. Biologically active substances, such as peptides, alkaloids, polyphenolic compounds, silymarin, antibiotics, fatty acids, vitamins, probiotics, synbiotics and lamiaceae have also demonstrated actions that combat NAFLD. Considering their different mechanisms of action, combining some of them may prove an efficacious treatment for NAFLD. In this light, the present review describes recent progress and future prospects in treating NAFLD.

Hepatoprotective dibenzocyclooctadiene lignans from the fruits of Kadsura coccinea.

The phytochemical investigations on the fruits of Kadsura coccinea led to the isolation of six undescribed dibenzocyclooctadiene lignans named kadcolignans B-G, together with eleven previously described analogues. The structures of these compounds were established by spectroscopic methods including NMR, HRESIMS, and CD experiments. All isolated compounds were evaluated for their hepatoprotective activity by measuring the levels of triglyceride (TG), total cholesterol (TC), and reactive oxygen species (ROS) in FFA-induced HepG2 cells. As a result, compounds 4, 5, 9, 13, and 15 showed potent inhibitory effects on hepatocyte lipid accumulation at a concentration of 100 µM. Our research not only broadens the understanding on the chemical composition of K. coccinea but also provides experimental and theoretical evidences supporting the fruit's active ingredients in alleviating nonalcoholic fatty liver disease (NAFLD).

The zebrafish embryo as a model for chemically-induced steatosis: a case study with three pesticides.

There is an increasing incidence and prevalence of fatty liver disease in the western world, with steatosis as the most prevalent variant. Known causes of steatosis include exposure to food-borne chemicals, and overconsumption of alcohol, carbohydrates and fat, and it is a well-known side effect of certain pharmaceuticals such as tetracycline, amiodarone and tamoxifen (drug-induced hepatic steatosis). Mechanistic knowledge on chemical-induced steatosis has greatly evolved and has been organized into adverse outcome pathways (AOPs) describing the chain of events from first molecular interaction of a substance with a biological system to the adverse outcome, intrahepatic lipid accumulationIn this study, three known steatosis-inducing pesticides (imazalil, clothianidin, and thiacloprid) were tested for their ability to induce hepatic triglyceride accumulation in the zebrafish (Danio rerio) embryo (ZFE) at 5 days post fertilization, both as single compounds and equipotent binary mixtures. The results indicate that the ZFE is very well applicable as a higher tier testing model to confirm effects in downstream key events in AOPs, that is, chemically-induced triglyceride accumulation in the whole organism and production of visible steatosis. Moreover, dose addition could be concluded for binary mixtures of substances with similar and with dissimilar modes of action.

Monascus red pigments alleviate high-fat and high-sugar diet-induced NAFLD in mice by modulating the gut microbiota and metabolites.

Monascus red pigments (MRP) may have benefits against NAFLD with an unclear mechanism. This study aimed to explore the protective effect of MRP supplementation against NAFLD through regulation of gut microbiota and metabolites. The C57BL/6 mice animals were randomly allocated into the normal diet (NC), HFHS diet-induced NAFLD model, and MRP intervention group fed with HFHS diet. Serum lipid profiles and liver function parameters were measured. Liver and colon histopathology analysis was conducted to determine the injury in the liver and colon. 16S rRNA gene sequencing was employed to analyze gut microbial composition from fecal samples. Untargeted metabonomics was performed to analyze changes in metabolites in serum and fecal samples. MRP supplementation significantly improved the HFHS-induced alterations in body weight, lipid profiles, and liver function (p < .01). MRP supplementation decreased the abundance of Akkermansia, Candidatus saccharimonas, Dubosiella, and Oscillibacter, while increasing Lactobacillus, Lachnospiraceae NK4A136 group, and Rikenella in mice fed the HFHS diet. Furthermore, MRP supplementation improved the serum and fecal metabolic profiles induced by the HFHS diet, primarily involving the arachidonic acid metabolism, unsaturated fatty acid biosynthesis, and adipocyte lipolysis pathways. Liver function and lipid profiles were closely associated with the abundance of Lactobacillus, Streptococcus, Oscillibacter, Akkemansia, and Desulfovibrio (p < .01). These findings revealed that MRP supplementation may help restore gut microbiota composition and balance its metabolites, thereby improving NAFLD. This study presents a novel outlook on the potential benefits of MRP supplementation in ameliorating NAFLD and supports the application of MRP as a new functional food.

Polyphenols improve non-alcoholic fatty liver disease via gut microbiota: A comprehensive review.

Polyphenols, natural micronutrients derived from plants, are valued for their anti-inflammatory and antioxidant properties. The escalating global prevalence of non-alcoholic fatty liver disease (NAFLD) underscores its status as a chronic progressive liver condition. Furthermore, the dysregulation of gut microbiota (GM) is implicated in the onset and progression of NAFLD through the actions of metabolites such as bile acids (BAs), lipopolysaccharide (LPS), choline, and short-chain fatty acids (SCFAs). Additionally, GM may influence the integrity of the intestinal barrier. This review aims to evaluate the potential effects of polyphenols on GM and intestinal barrier function, and their subsequent impact on NAFLD. We searched through a wide range of databases, such as Web of Science, PubMed, EMBASE, and Scopus to gather information for our non-systematic review of English literature. GM functions and composition can be regulated by polyphenols such as chlorogenic acid, curcumin, green tea catechins, naringenin, quercetin, resveratrol, and sulforaphane. Regulating GM composition improves NAFLD by alleviating inflammation, liver fat accumulation, and liver enzymes. Furthermore, it improves serum lipid profile and gut barrier integrity. All of these components affect NAFLD through the metabolites of GM, including SCFAs, choline, LPS, and BAs. Current evidence indicates that chlorogenic acid, resveratrol, quercetin, and curcumin can modulate GM, improving intestinal barrier integrity and positively impacting NAFLD. More studies are necessary to evaluate the safety and efficacy of naringenin, sulforaphane, and catechin.

Insufficient FUNDC1-dependent mitophagy due to early environmental cadmium exposure triggers mitochondrial redox imbalance to aggravate diet-induced lipotoxicity.

Cadmium (Cd) is a toxic contaminant widely spread in natural and industrial environments. Adolescent exposure to Cd increases risk for obesity-related morbidity in young adults including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite this recognition, the direct impact of adolescent Cd exposure on the progression of MASLD later in life, and the mechanisms underlying these effects, remain unclear. Here, adolescent rats received control diet or diets containing 2 mg Cd2+/kg feed for 4 weeks, and then HFD containing 15% lard or control diet in young adult rats was selected for 6 weeks to clarify this issue. Data firstly showed that HFD-fed rats in young adulthood due to adolescent Cd exposure exhibited more severe MASLD, evidenced by increased liver damage, disordered serum and hepatic lipid levels, and activated NLRP3 inflammasome. Hepatic transcriptome analysis revealed the potential effects of mitochondrial dysfunction in aggravated MASLD due to Cd exposure. Verification data further confirmed that mitochondrial structure and function were targeted and disrupted during this process, shown by broken mitochondrial ridges, decreased mitochondrial membrane potential, imbalanced mitochondrial dynamic, insufficient ATP concentration, and enhanced mitochondrial ROS generation. However, mitophagy is inactively involved in clearance of damaged mitochondria induced by early Cd in HFD condition due to inhibited mitophagy receptor FUNDC1. In contrast, FUNDC1-dependent mitophagy activation prevents lipotoxicity aggravated by early Cd via suppressing mitochondrial ROS generation. Collectively, our data show that insufficient FUNDC1-dependent mitophagy can drive the transition from HFD-induced MASLD to MASH, and accordingly, these findings will provide a better understanding of potential mechanism of diet-induced metabolic diseases in the context of early environmental Cd exposure.

Effect of Ilex hainanensis Merr. On HFD-induced nonalcoholic fatty liver disease and rebalance of gut microbiota and bile acids metabolism in mice.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by excessive intracellular fat deposition in the hepatocytes, and the development is exacerbated by gut microbiota and bile acids metabolism disorders. Ilex hainanensis Merr. is a traditional medicine of the Zhuang nationality, historically esteemed for its efficacy in lowering blood pressure and lipid levels. This study aimed to investigate the pharmacodynamic effects in NAFLD mice and impacts on gut microbiota and bile acids (BAs) metabolism of I. hainanensis extract (IHA). 16 compounds were identified from IHA by HPLC-DAD-MS analysis. IHA significantly reduced body weight indexs, alanine transaminase (ALT) and aspartate transaminase (AST) activities, improved dyslipidemia and insulin resistance (IR), and effectively ameliorated hepatic steatosis in HFD-induced NAFLD mice. IHA also altered gut microbiota composition, particularly enhancing the abundance of bacteria involved in BAs metabolism, as well as augmented BAs synthesis in the liver and increased fecal excretion. In conclusion, our findings suggest that IHA holds promise in improving NAFLD conditions and modulating gut microbiota and BAs metabolism. These insights contribute to a deeper understanding of the mechanisms underlying IHA-mediated alleviation of lipid accumulation in NAFLD.

Baseline and change in serum lipid and uric acid level over time and incident of nonalcoholic fatty liver disease (NAFLD) in Chinese adults.

Observational studies have shown that non-alcoholic fatty liver disease (NAFLD) is strongly associated with metabolic dysfunction. However, there is a paucity of research on whether changes in indicators of serum metabolism contribute to the development of NAFLD. This study was conducted with 4084 participants who underwent healthy physical examinations at Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China, in 2022 and 2023. Baseline and follow-up measurements, including anthropometric data, abdominal ultrasound and blood samples were collected. The diagnosis of NAFLD was based on the 2010 Chinese Guidelines on Diagnosis and Treatment of NAFLD. Multiple logistic regression was utilized to analyze the odds ratios (ORs) for the 1-year risk of NAFLD in connection with both baseline metabolic indicators and changes in metabolic indicators observed over the course of 1 year. A total of 3425 study participants who were free of NAFLD at baseline, including 1146 men and 2279 women, were included in the final analysis. The mean age was 34.43 ± 7.20 years. Participants who developed NAFLD were older, male and had higher levels of body mass index (BMI), blood pressure, fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), free triiodothyronine (fT3), uric acid (UA), alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and lower levels of high-density lipoprotein cholesterol (HDL-C) and free thyroxine (fT4) (all P values < 0.05). The multivariable model showed that baseline BMI, diastolic blood pressure (DBP), TG, TC, HDL-C, LDL-C, UA, fT4, fT3, ALT and changes in TG, HDL-C, and UA were associated with the 1-year risk of developing NAFLD. The risk of NAFLD increased by 56% [OR 1.56, 95% Confidence Interval (CI) 1.32-1.87] and 40% (OR 1.40, 95% CI 1.19-1.64) for each standard deviation (SD) increase in altered TG values (1.01 mmol/L) and altered UA values (55 µmol/L) respectively. Conversely, for each SD (0.27 mmol/L) increase in HDL-C change, the 1-year risk of incident NAFLD was reduced by 50% (OR 0.50, 95% CI 0.40-0.62). The present study suggested that increases in TG and UA, and decreases in HDL-C, significantly increase the risk of developing NAFLD. Therefore, more attention should be paid to these factors in the management and prevention of NAFLD.

Effect of Supplementation of a Butyrate-Based Formula in Individuals with Liver Steatosis and Metabolic Syndrome: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

Postbiotics could exert different metabolic activities in animal models of non-alcoholic fatty liver disease (NAFLD) and in humans affected by metabolic syndrome. This is a randomized, double-blind, placebo-controlled, parallel-group clinical trial that enrolled a sample of 50 Caucasian healthy individuals with NAFLD, defined as liver steatosis, and metabolic syndrome. After a 4-week run-in, the enrolled individuals were randomized to take a food for special medical purposes with functional release, one tablet a day, containing calcium butyrate (500 mg/tablet), zinc gluconate (zinc 5 mg/tablet), and vitamin D3 (500 IU/tablet), or an identical placebo for 3 months. Liver and metabolic parameters were measured at baseline and at the end of the study. No subject experienced any adverse events during the trial. In both groups, a significant decrease in total cholesterol (TC) and triglycerides (TG) plasma levels was observed at the randomization visit vs. pre-run-in visit (p < 0.05). Regarding liver parameters, after treatment, the fatty liver index (FLI) improved significantly vs. baseline values (p < 0.05) and vs. placebo group (p < 0.05) in the active treatment group, and the hepatic steatosis index (HSI) improved significantly vs. baseline values (p < 0.05). Moreover, after active treatment, TC, TG, and gamma-glutamyl transferase (gGT) improved significantly vs. baseline values (p < 0.05), and TC and TG improved vs. placebo group (p < 0.05), as well. In the placebo group, liver parameters remained unchanged after treatment; only TG improved significantly vs. baseline values (p < 0.05). In our study, we observed that the butyrate-based formula improved FLI and plasma lipid patterns in individuals affected by liver steatosis and metabolic syndrome.

Efficacy of Ultrasound for the Detection of Possible Fatty Liver Disease in Children.

Pediatric MASLD (previously referred to as NAFLD) incidence has continued to rise along with the obesity pandemic. Pediatric MASLD increases the risk of liver fibrosis and cirrhosis in adulthood. Early detection and intervention can prevent and reduce complications. Liver biopsy remains the gold standard for diagnosis, although imaging modalities are increasingly being used. We performed a retrospective study of 202 children seen in a pediatric gastroenterology clinic with a complaint of abdominal pain, elevated liver enzymes or MASLD, or a combination of the three to evaluate screening methods for MASLD. A total of 134 of the 202 patients included in the study underwent laboratory testing and abdominal ultrasound. Ultrasound images were reviewed with attention to liver size and echotexture by a fellowship-trained pediatric radiologist for liver size and echotexture. Overall, 76.2% of the initial radiology reports correctly identified hepatomegaly based on age and 75.4% of the initial radiology reports correctly described hepatic echogenicity that was consistent with increased hepatic fat deposition. Use of screening ultrasound in concert with other clinical evaluations can be helpful to identify children at risk of MASLD. Utilizing ranges for liver span according to age can help to diagnose hepatomegaly, and understanding how to identify hepatic echogenicity is important for identifying possible hepatic steatosis.