Fatty Liver Research Articles

Ginsenoside, a potential natural product against liver diseases: a comprehensive review from molecular mechanisms to application.

Liver disease constitutes a significant cause of global mortality, with its pathogenesis being multifaceted. Identifying effective pharmacological and preventive strategies is imperative for liver protection. Ginsenosides, the major bioactive compounds found in ginseng, exhibit multiple pharmacological activities including protection against liver-related diseases by mitigating liver fat accumulation and inflammation, preventing hepatic fibrosis, and exerting anti-hepatocarcinogenic effects. However, a comprehensive overview elucidating the regulatory pathways associated with ginsenosides in liver disease remains elusive. This review aims to consolidate the molecular mechanisms through which different ginsenosides ameliorate distinct liver diseases, alongside the pathogenic factors underlying liver ailments. Notably, ginsenosides Rb1 and Rg1 demonstrate significantly effective in treating fatty liver, hepatitis, and liver fibrosis, and ginsenosides CK and Rh2 exhibit potent anti-hepatocellular carcinogenic effects. Their molecular mechanisms underlying these effects primarily involve the modulation of AMPK, NF-κB, TGF-β, NFR2, JNK, and other pathways, thereby attenuating hepatic fat accumulation, inflammation, inhibition of hepatic stellate cell activation, and promoting apoptosis in hepatocellular carcinoma cells. Furthermore, it provides insights into the safety profile and current applications of ginsenosides, thereby facilitating their clinical development. Consequently, ginsenosides present promising prospects for liver disease management, underscoring their potential as valuable therapeutic agents in this context.

Association of changes in the type 2 diabetes and MASLD/related SLD status with risk of developing cardiovascular disease.

This study assessed the association of remission of type 2 diabetes mellitus (DM) or metabolic dysfunction-associated steatotic liver disease (MASLD)/related SLD (r-SLD; MASLD with excessive alcohol intake) as defined by the fatty liver index with the risk of cardiovascular disease (CVD). Health examination data at baseline and after 2 years (2-Years) were extracted from a nationwide claims database in Japan. Among participants aged 18-72 years with at least 3 years of follow-up, 9345 participants with DM-associated MASLD/r-SLD and 71 932 participants with non-DM MASLD/r-SLD at baseline were included in the study. The participants were stratified by the achievement of remission of MASLD/r-SLD or DM at 2-Years. In each group after stratification, the risk of new-onset CVD during the observation period was analysed using multivariate Cox proportional hazards models. During a median follow-up of 4.9 years (starting from 2-Years), 1368 cases of CVD were observed. The hazard ratio (95% confidence interval) for CVD was 0.50 (0.31-0.80) for participants with remission of DM, 0.65 (0.47-0.91) for participants with remission of MASLD/r-SLD, and 0.34 (0.15-0.77) for participants with remission of both DM and MASLD/r-SLD. Conversely, remission of MASLD/r-SLD was not linked to a reduced risk of CVD in participants with non-DM MASLD/r-SLD. The association of MASLD/r-SLD remission with CVD risk differs greatly in the presence and absence of DM. In patients with DM-MASLD/r-SLD, MASLD/r-SLD remission can significantly reduce CVD risk similarly as remission of DM.

Comparative application of MAFLD and MASLD diagnostic criteria on NAFLD patients: insights from a single-center cohort

The diagnostic criteria for Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) and Metabolic Associated Steatotic Liver Disease (MASLD) aim to refine the classification of fatty liver diseases previously grouped under Non-Alcoholic Fatty Liver Disease (NAFLD). This study evaluates the applicability of the MAFLD and MASLD frameworks in NAFLD patients, exploring their clinical utility in identifying high-risk patients. A total of 369 NAFLD patients were assessed using MAFLD and MASLD diagnostic criteria. Baseline characteristics, metabolic profiles, hepatic fibrosis, and cardiovascular risks were compared across the groups. Among NAFLD patients, 97.55% (n = 359) met MASLD criteria, and 97.01% (n = 357) fulfilled MAFLD criteria. Both frameworks MAFLD and MASLD captured overlapping populations, with MASLD encompassing slightly more cases. No significant differences were observed in metabolic risk factors, fibrosis indices (APRI, FIB-4, NAFLD fibrosis score), or cardiovascular risk (10-year ASCVD score). A small subset of lean NAFLD patients (10 cases) with distinct profiles remained uncategorized by either framework. Pure NAFLD cases (n = 10) were with mild insulin resistance (HOMA-IR: 3.07 ± 0.33) and slightly elevated LDL (102.5 ± 42.87 mg/dL), while fibrosis indices indicated low fibrosis risk. Steatosis indices supported the diagnosis of early-stage NAFLD with preserved liver function. These patients do not meet the criteria for inclusion in the MAFLD or MASLD frameworks, highlighting a gap in the current diagnostic systems. MAFLD and MASLD criteria align closely with NAFLD in capturing patients with metabolic risk with MASLD-enhanced inclusivity. Further refinement is required to address heterogeneity, particularly in lean NAFLD patients. Hypertension prevalence was comparable (17.4% in NAFLD, 18.2% in MAFLD, 17.8% in MASLD; p = 0.960), as was diabetes mellitus (36.7%, 37.8%, and 37.6%, respectively; p = 0.945). Body mass index was also similar across groups, with medians of 33.25, 33.6, and 33.4 kg/m2 (p = 0.731). Non-invasive markers of hepatic fibrosis, including APRI, FIB-4, and NAFLD fibrosis scores, did not differ significantly, with median FIB-4 scores around 1.05 (p = 0.953). Similarly, were the results of hepatic steatosis index and ASCVD score.

The association between working hours and working type with non-alcoholic fatty liver disease: results from the NHANES 1999-2014

BackgroundPrevious research has indicated that long working hours are connected to a variety of health conditions, including nonalcoholic fatty liver disease (NAFLD). However, this association which has been observed in more population is limited. Our research is designed to evaluate the association between working hours, working type, and NAFLD.MethodsThe study comprised adults with complete details on working hours, working type, and NAFLD from the NHANES 1999-2014. We employed the hepatic steatosis index (HSI) to evaluate NAFLD and examined the relationship between working hours or working type and hepatic steatosis using weighted multiple-variable regression models and restricted cubic spline (RCS) analysis. In addition, further subgroup analysis was performed based on sex, age, ratio of family income to poverty (PIR), education, and diabetes.ResultsLong working hours were significantly linked to an elevated risk of NAFLD (OR: 1.57, 95%CI: 1.21-2.05), even after controlling for confounding factors. RCS analysis suggested that there was no nonlinear relationship between them. When weekly working hours > 50, the likelihood of NAFLD among the population heightened to 57% and this risk increased to 99% in the female population. As for working type, increasing physical intensity of work was associated with higher NAFLD risk, but only heavy manual labor continued to show significance after adjustment (OR:1.39, 95%CI: 1.06-1.81). We observed that the relationship between heavy manual labor and NAFLD was more significant in the older and male populations.ConclusionOur results indicate that long working hours and engaging in heavy physical labor are independent risk factors for NAFLD. As working hours increase and individuals engage in heavy physical labor for extended periods, the risk of developing NAFLD significantly rises.

BMI trajectories are associated with NAFLD and advanced fibrosis via aging-inflammation mediation

BackgroundAs the global epidemic of obesity fuels metabolic conditions, the burden of nonalcoholic fatty liver disease (NAFLD) will become enormous. Abundant studies revealed the association between high body mass index (BMI) and NAFLD but overlooked the BMI patterns across life stages. We aimed to explore how BMI trajectories over age relate to NAFLD.MethodsSelecting 3212 participants in NHANES 2017–2020, we tracked BMI records at different ages. Using a latent class trajectory model (LCTM), we identified BMI trajectories over age. Multinomial logistic regression assessed their association with NAFLD and advanced fibrosis. Structural equation modeling (SEM) revealed mediation effects.ResultsWe identified 3 BMI trajectories: Steady Progression, Increase to Decrease, and Rapid Ascending. There was no significant difference in NAFLD/advanced fibrosis risk between the increase-to-decrease group and the steady progression group. The Rapid Ascending trajectory significantly correlated with NAFLD (OR = 2.21, 95% CI 1.29–3.77) and advanced fibrosis (OR = 3.04, 95% CI 1.13–8.22). This association was influenced by a chain-mediated process of phenotypic age and C-reactive protein (mediated effect to NAFLD = 0.010, p < 0.01; mediated effect to advanced fibrosis = 0.003, p < 0.05). This mediation on NAFLD was independent of insulin resistance (IR). The association between rapid ascending trajectory and advanced fibrosis was more pronounced among the male subgroup (p for interaction = 0.008).ConclusionThe rapid ascending trajectory of BMI correlates with an increased susceptibility to NAFLD and advanced fibrosis independent of BMI, mediated by aging and inflammation. Our results suggest that long-term maintenance of BMI is pivotal in NAFLD prevention. Aging-inflammation may represent a distinct mechanism of sustained obesity to NAFLD, independent of IR.

Gut microbiome in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has a rapidly growing incidence worldwide, affecting approximately one-third of world population. The disturbance of gut commensal bacteria impacting host’s homeostasis is referred to as gut dysbiosis. The gut microbiome contributes to the pathogenesis of NAFLD through various pathways. Gut microbiota is at constant interactions with the intestinal epithelial barrier and affects its integrity. Through gut-liver axis, gut microbiota may influence liver immune function. The release of lipopolysaccharides (LPS) from intestines to portal vein which are transported to the liver, may trigger hepatic inflammation, steatosis and even fibrosis. Moreover, the gut microbiome induces the conversion of primary bile acids (BAs) to secondary BAs, which activates intestinal receptors, such as FXR and TGR5. FXR activation decreases fat absorption and thus reduces hepatic lipid accumulation, while TGR5 activation promotes the release of glucagon-like peptide-1 (GLP-1) in blood. Furthermore, gut ethanol-producing bacteria has been implicated in NAFLD development. Additionally, in NAFLD there is a reduction in intestinal levels of short-chain fatty acids, such as butyrate, propionate and acetate. Many bacterial alterations have been observed in NAFLD, including the increased Bacteroidetes and decreased Firmicutes. Many probiotics have been tried in NAFLD prevention and management, including a plethora of strains from Lactobacilli, Bifidobacteria and Streptococcus and some of them have promising perspectives. There is also some promising data from the administration of prebiotics (such as inulin and fructo-oligosaccharides) and symbiotics (probiotics plus prebiotics). Faecal microbiota transplantation (FMT) is yet to be evaluated for its efficacy against NAFLD.

Discovery of robust and highly specific microbiome signatures of non-alcoholic fatty liver disease

BackgroundThe pathogenesis of non-alcoholic fatty liver disease (NAFLD) with a global prevalence of 30% is multifactorial and the involvement of gut bacteria has been recently proposed. However, finding robust bacterial signatures of NAFLD has been a great challenge, mainly due to its co-occurrence with other metabolic diseases.ResultsHere, we collected public metagenomic data and integrated the taxonomy profiles with in silico generated community metabolic outputs, and detailed clinical data, of 1206 Chinese subjects w/wo metabolic diseases, including NAFLD (obese and lean), obesity, T2D, hypertension, and atherosclerosis. We identified highly specific microbiome signatures through building accurate machine learning models (accuracy = 0.845–0.917) for NAFLD with high portability (generalizable) and low prediction rate (specific) when applied to other metabolic diseases, as well as through a community approach involving differential co-abundance ecological networks. Moreover, using these signatures coupled with further mediation analysis and metabolic dependency modeling, we propose synergistic defined microbial consortia associated with NAFLD phenotype in overweight and lean individuals, respectively.ConclusionOur study reveals robust and highly specific NAFLD signatures and offers a more realistic microbiome-therapeutics approach over individual species for this complex disease.E4koFqVmYng21Zwjp47efAVideo

Prospects of elafibranor in treating alcohol-associated liver diseases

Alcohol-related liver disease (ALD), which is induced by excessive alcohol consumption, is a leading cause of liver-related morbidity and mortality. ALD patients exhibit a spectrum of liver injuries, including hepatic steatosis, inflammation, and fibrosis, similar to symptoms of nonalcohol-associated liver diseases such as primary biliary cholangitis, metabolic dysfunction-associated steatotic liver disease, and nonalcoholic steatohepatitis. Elafibranor has been approved for the treatment of primary biliary cholangitis and has been shown to improve symptoms in both animal models and in vitro cell models of metabolic dysfunction-associated steatotic liver disease and nonalcoholic steatohepatitis. However, the efficacy of elafibranor in treating ALD remains unclear. In this article, we comment on the recent publication by Koizumi et al that evaluated the effects of elafibranor on liver fibrosis and gut barrier function in an ALD mouse model. Their findings indicate the potential of elafibranor for ALD treatment, but further experimental investigations and clinical trials are warranted.

Correlation of sarcopenia with progression of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease: a study from two cohorts in China and the United States

ObjectiveThe objective of this study was to investigate the association between sarcopenia and liver fibrosis in patients aged 18–59 years with metabolic dysfunction-associated steatotic liver disease (MASLD) and to assess the potential of sarcopenia as a risk factor for the progression of liver fibrosis.MethodsThe study included 821 patients with MASLD in the US cohort and 3,405 patients with MASLD in the Chinese cohort. Liver controlled attenuation parameters (CAP) and liver stiffness measurements (LSM) were assessed by vibration-controlled transient elastography (VCTE) to evaluate the extent of hepatic steatosis and fibrosis. Sarcopenia was assessed by measuring appendicular skeletal muscle mass (ASM) and calculating ASMI. To analyze the relationship between sarcopenia, ASMI, and liver fibrosis, logistic regression models, multivariate-adjusted models, and restricted cubic spline (RCS) models were employed, with stratification and interaction analyses.ResultsThe results demonstrated that patients with sarcopenia exhibited a markedly elevated risk of significant liver fibrosis, advanced liver fibrosis, and cirrhosis compared to those without sarcopenia in both cohorts. After adjusting for confounding variables, sarcopenia was identified as an independent risk factor for the progression of liver fibrosis in patients with MASLD. A significant negative correlation was observed between ASMI and the severity of liver fibrosis, with a progressive reduction in the risk of liver fibrosis associated with increasing ASMI. Additionally, a non-linear feature was evident in some liver fibrosis indicators. Subgroup analysis further corroborated the finding that the harmful effect of sarcopenia on liver fibrosis was consistent across all identified subgroups.ConclusionSarcopenia may be associated with the progression of liver fibrosis in patients with MASLD. Monitoring ASMI may assist in identifying individuals at an elevated risk of liver fibrosis in MASLD patients.

CD44 in myEloid cells is a major driver of liver inflammation and injury in alcohol-related liver disease.

Alcohol-related liver disease (ALD) is one of the leading causes of severe liver disease with limited pharmacological treatments for alcohol-related steatohepatitis (ASH). CD44, a glycoprotein mainly expressed in immune cells, has been implicated in multiple inflammatory diseases but has never been studied in the ALD context. We therefore studied its contribution to ASH development in mice and its expression in ALD patients. Here, we report that liver CD44 expression is associated with liver injury and inflammation and its deficiency (Cd44-/-) partially protected mice upon chronic plus binge ethanol feeding (CPB-EtOH). CD44 deletion in myeloid cells (Cd44myel-KO) recapitulated the same protective effects associated with reduced inflammatory monocyte infiltration and neutrophil activation in the liver and diminished blood neutrophil-lymphocyte ratio (NLR). CD44-deficient neutrophils displayed reduced PMA-induced inflammatory mediator expression and increased phagocytosis of live bacteria. Cd44myel-KO mice were also protected against hepatic steatosis mediated by CPB-EtOH or chronic ethanol feeding, due in part to increased SIRT1 mediated fatty acid beta-oxidation. CD44 neutralization with antibodies strongly decreased liver injury and inflammation (hepatic neutrophil frequency) and blood NLR upon CPB-EtOH. In samples from ALD patients, hepatic CD44 expression increased with ALD severity, correlated with hepatic TNFα and CD11b expression, and CD44-expressing neutrophils were enriched in alcohol-associated hepatitis. Human and experimental evidence supports CD44 as a marker of hepatic inflammation in ALD. In addition, CD44 modulates neutrophil mobilization and functions and its targeting partially prevents liver inflammation and injury in the context of acute-on-chronic alcohol drinking.

Transitioning from NAFLD to MAFLD and MASLD: the toxic relationship with alcohol consumption

Alcohol is a well-known toxic etiologic factor for liver injury. Metabolic substrates of alcohol (especially acetaldehyde) have a major responsibility and genetic susceptibility, alterations in microbiota and immune system are important co-factors for this injury. Major injury in liver is hepatocellular lipid accumulation. Therefore the relationship between non-alcoholic and alcoholic fatty liver diseases should have been defined clearly. Recently two major liver committees adopted new terminologies such as metabolic-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related liver disease (MetALD), and alcoholic liver disease (ALD) instead of non-alcoholic fatty liver disease (NAFLD). These terminologies were based on the effects of metabolic syndrome on liver. Alcohol consumption was defined differently according to these nomenclatures. MAFLD defined alcohol intake (regardless of amount) as “dual etiology fatty liver disease” and the Delphi consensus defined MASLD, MetALD, or ALD according to daily consumption of alcohol amount.

Effects of the SGLT2 inhibitor ipragliflozin and metformin on hepatic steatosis and liver fibrosis: Sub-analysis of a randomized controlled study.

To compare the effects of ipragliflozin, a sodium-dependent glucose transporter-2 inhibitor, and those of metformin on the visceral fat area (VFA), a prospective, multi-centre, open-label, blinded-endpoint, randomized, controlled study was undertaken. The generated data were used to examine the effects of ipragliflozin and metformin on indices of hepatic steatosis and liver fibrosis. In total, 103 Japanese patients with type-2 diabetes (T2D), body mass index (BMI) of ≥22 kg/m2 and glycated haemoglobin level of 7%-10% were randomly administered ipragliflozin 50 mg or metformin 1000 mg for 24 weeks. Various parameters, including hepatic steatosis indices, fatty liver index (FLI), hepatic steatosis index (HSI), non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS), liver fibrosis indices, AST to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index, were compared in the sub-analyses. The correlations between changes in each index and VFA were evaluated. At baseline, patients demonstrated moderate hepatic steatosis, with FLI scores of 52.9 ± 26.6 and 57.8 ± 29.0 in the ipragliflozin and metformin groups, respectively. At 24 weeks, compared with metformin, ipragliflozin showed improvements in hepatic steatosis indices: FLI (-9.24 ± 10.7 vs. -3.45 ± 11.8, p = 0.013), HSI (-1.45 ± 2.32 vs. -0.45 ± 1.87, p = 0.021), NAFLD-LFS (-0.70 ± 1.46 vs. -0.04 ± 0.98, p = 0.011) and liver fibrosis index: APRI (-0.110 ± 0.323 vs. 0.033 ± 0.181, p = 0.010). In the ipragliflozin group, changes in FLI and HSI were correlated with VFA reduction (r = 0.340, p = 0.024; r = 0.367, p = 0.011, respectively). Compared with metformin, ipragliflozin improved multiple hepatic steatosis and liver fibrosis indices, suggesting that ipragliflozin exerts potential hepatoprotective effects in early-stage liver disease associated with T2D.

Fructose catabolism and its metabolic effects: Exploring host-microbiota interactions and the impact of ethnicity.

Important health disparities are observed in the prevalence of obesity and associated non-communicable diseases (NCDs), including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) among ethnic groups. Yet, the underlying factors accounting for these disparities remain poorly understood. Fructose has been widely proposed as a potential mediator of these NCDs, given that hepatic fructose catabolism can result in deleterious metabolic effects, including insulin resistance and hepatic steatosis. Moreover, the fermentation of fructose by the gut microbiota can produce metabolites such as ethanol and acetate, both which serve as potential substrates for de novo lipogenesis (DNL) and could therefore contribute to the development of these metabolic conditions. Significant inter-ethnic differences in gut microbiota composition have been observed. Moreover, fructose consumption varies across ethnic groups, and fructose intake has been demonstrated to significantly alter gut microbiota composition, which can influence its fermenting properties and metabolic effects. Therefore, ethnic differences in gut microbiota composition, which may be influenced by variations in fructose consumption, could contribute to the observed health disparities. This review provides an overview of the complex interactions between host and microbial fructose catabolism, the role of ethnicity in shaping these metabolic processes and their impact on host health. Understanding these interactions could provide insights into the mechanisms driving ethnic health disparities to improve personalized nutrition strategies. KEY POINTS: Dietary fructose consumption has increased substantially over recent decades, which has been associated with the rising prevalence of obesity and non-communicable diseases (NCDs) such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Pronounced disparities among different ethnic groups in NCD prevalence and dietary fructose consumption underscore the need to elucidate the underlying mechanisms of fructose catabolism and its health effects. Together with the well-known toxic effects of hepatic fructose catabolism, emerging evidence highlights a role for the small intestinal microbiota in fermenting sugars like fructose into various bacterial products with potential deleterious metabolic effects. There are significant ethnic differences in gut microbiota composition that, combined with varying fructose consumption, could mediate the observed health disparities. To comprehensively understand the role of the gut microbiota in mediating fructose-induced adverse metabolic effects, future research should focus on the small intestinal microbiota. Future research on fructose - microbiota - host interactions should account for ethnic differences in dietary habits and microbial composition to elucidate the potential role of the gut microbiota in driving the mentioned health disparities.

Hepatotoxicity of Three Common Liquid Crystal Monomers in Mus musculus: Differentiation of Actions Across Different Receptors and Pathways.

Liquid crystal monomers (LCMs) of different chemical structures were widely detected in various environmental matrices. However, their health risk evaluation is lacking. Herein, three representative LCMs were selected from 74 LCM candidates upon literature review and acute cytotoxicity evaluation, then Mus musculus were exposed to the three LCMs for 42 days at doses of 0.5 and 50 μg/kg/d to investigate hepatotoxicity and mechanisms. Phenotypic and histopathological results showed that the three LCMs (DTMDPB, MeO3bcH, and 5OCB) induced hepatomegaly, and only 5OCB induced fatty liver. DTMDPB and MeO3bcH decreased the total cholesterol (TCHO) and triglyceride (TG) content, whereas 5OCB increased the TCHO, TG, and alanine aminotransferase levels. Transcriptome and molecular docking analysis revealed that DTMDPB induced hepatotoxicity by agonizing the farnesoid X receptor, resulting in the disruption of unsaturated fatty acid biosynthesis, ascorbic acid and antioxidant pathways, and circadian clock homeostasis. MeO3bcH promoted inflammation and altered unsaturated fatty acid, primary bile acid biosynthesis, and circadian rhythm by antagonizing the aryl hydrocarbon receptor. 5OCB antagonized peroxisome proliferator-activated receptors, leading to fatty liver caused by the disruption of steroid, cholesterol, and terpenoid backbone biosynthesis pathways. This study provides references for understanding the hepatotoxicity of LCMs with different structures and the selection of priority control LCMs.

A hypocaloric protein-rich diet before metabolic surgery improves liver function in patients with obesity and diabetes

PurposeObesity and type 2 diabetes (T2DM) are major risk factors for hepatic steatosis. Diet or bariatric surgery can reduce liver volume, fat content, and inflammation. However, little is known about their effects on liver function, as evaluated here using the LiMAx test.MethodsIn the MetaSurg study (RCT on the effects of different Roux-en-Y gastric bypass (RYGB) limb lengths on diabetes remission in patients with BMI ≥ 27 to ≤ 60 kg/m2 and T2DM; trial registration: DRKS00007810, German Clinical Trials Register Freiburg), 24 consecutive patients underwent liver function (LiMAx) and imaging assessments (MRI, transient elastography; TE) before and after diet and surgery. Two weeks before surgery, the patients received a hypocaloric protein-rich diet.ResultsNine of 18 patients had a pathologic LiMAx value (≤ 315 µg/kg/h) at baseline. After two weeks of diet, LiMAx values improved (p = 0.01, paired t test, n = 15). LiMAx values further recovered six months after RYGB (p = 0.01, paired t test, n = 15), which was accompanied by decreased liver volumes (p = 0.005, paired t test, n = 10), proton density fat fraction (p = 0.003, paired t test, n = 12), and TE measurements (p = 0.032, paired t test, n = 14). The need for medical diabetes treatment decreased from 100 to 35%.ConclusionLiver function improved after a two-week hypocaloric protein-rich diet and metabolic surgery in patients with obesity and T2DM. These data suggest that a two-week diet for this group of patients prior to abdominal surgery could improve a presumably impaired liver function.

Bioinformatic Analysis for Exploring Target Genes and Molecular Mechanisms of Cadmium-Induced Nonalcoholic Fatty Liver Disease and Targeted Drug Prediction.

Cadmium (Cd) is a widely available metal that has been found to have a role in causing nonalcoholic fatty liver disease (NAFLD). However, the detailed toxicological targets and mechanisms by which Cd causes NAFLD are unknown. Therefore, the present work aims to reveal the main targets of action, cellular processes, and molecular pathways by which cadmium causes NAFLD. As shown in the bioinformatics analysis, there were 74 main targets of action for cadmium-induced NAFLD, hemopoietic cell kinase (HCK), EPH receptor A2 (EPHA2), MYC proto-oncogene (MYC), lysyl oxidase (LOX), dipeptidyl peptidase 7 (DPP7), nuclear factor erythroid 2-related factor 2 (NFE2L2), dual specificity phosphatase 6 (DUSP6), CD2 cytoplasmic tail binding protein 2 (CD2BP2), notch receptor 3 (NOTCH3), and phospholipase A2 group IVA (PLA2G4A) were screened as core genes. Testing these core genes in other databases, three differentially expressed genes, HCK, MYC, and DUSP6 were verified and used as targets for drug prediction in DsigDB; decitabine and retinoic acid were screened as potential therapeutic drugs for NAFLD based on the p-value and the combined score. The results of molecular docking showed that the predicted drugs can bind well to the core targets. In conclusion, cadmium is associated with NAFLD; the identified cadmium-toxicity targets, HCK, MYC, and DUSP6, may serve as biomarkers for the diagnosis of NAFLD and predicted drugs, decitabine and retinoic acid may have a potential role in the treatment of NAFLD.

The change of alanine aminotransferase distributions among US youths, NHANES 1988-2020.

The trend of alanine aminotransferase (ALT), a biomarker of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease), remains poorly described for the pediatric population because no widely accepted cutoffs are available to categorize ALT value. We described the nuanced changes in the distribution of ALT continuous values. We analyzed the data from 15,702 adolescents aged 12-19 who participated in the National Health and Nutrition Examination Surveys between 1988 and 2020. The ALT distributions were standardized for age and sex. The prevalence of elevated ALT was also assessed. The ALT geometric mean increased from 11.82 U/L in 1988-1994 to 17.24 U/L in 1999-2004, stayed above 17 U/L for a decade, and then decreased to 14.04 U/L in 2017-2020 (p for the quadratic trend <0.001). However, the 95th percentile of the ALT distribution remained above 35 U/L by the end of the study period after jumping from 26.02 U/L in 1988-1994 to 33.83 U/L in 1999-2004. The prevalence of elevated ALT (>42 U/L in boys and 30 U/L in girls), doubled from 1.53% (0.87%-2.19%) in 1988-1994 to 3.49% (2.73%-4.25%) in 1999-2004, and lingered around 4% through 2020. The ALT mean decreased in recent years, but the prevalence of elevated ALT remained persistently high. Population-wide reductions in fructose consumption may have contributed to the decrease in ALT mean. The stagnant right end of the distribution, manifesting as the high prevalence of elevated ALT, calls for intensified clinical prevention.

Association between Healthy Eating Index-2015 total and metabolic associated fatty liver disease in Americans: a cross-sectional study with U.S. National Health and Nutrition Examination Survey

BackgroundUtilizing the National Health and Nutrition Examination Survey (NHANES) dataset to investigate the relationship between dietary quality, as assessed by the Healthy Eating Index-2015 (HEI-2015), and the prevalence of metabolic associated fatty liver disease (MAFLD) among adults in the United States, our analysis revealed that an increased dietary quality was significantly correlated with a reduced risk of MAFLD in the American population.MethodThe NHANES dataset, encompassing the years 2017–2018 and comprising 3,557 participants, was incorporated into our analytical framework. Weighted multivariate linear regression model was performed to assess the linear relationship between the HEI-2015 and MAFLD. Dietary intake data were derived from two 24-h dietary recall interviews conducted as part of NHANES.ResultsFollowing multivariable adjustment, the weighted multivariable linear regression models demonstrated a negative correlation between the HEI-2015 total scores and the risk of MAFLD. The weighted logistic regression models revealed that each unit of increased HEI-2015 total value was associated with a 1.2% (95% CI: 0.9%, 1.5%; P &amp;lt; 0.001) decrease in the risk of f MAFLD. Upon categorization of the HEI-2015 scores into quartiles, the odds ratios (ORs) for the association between the risk of MAFLD and the quartile scores of HEI-2015, in comparison to the baseline quartile, were 0.945 (95% CI: 0.852–1.047; P = 0.279), 0.834 (95% CI: 0.750–0.927; P &amp;lt; 0.001), and 0.723 (95% CI: 0.646–0.811; P &amp;lt; 0.001), respectively. When participants were stratified by age and sex, subgroup analyses showed a similar trend. This pattern was also evident in the smooth curve fitting (SCF) and weighted generalized additive model (GAM).ConclusionElevated dietary quality, as assessed by the total and component food scores of the HEI-2015, was significantly correlated with a diminished risk of MAFLD among participants in the NHANES survey featured in this investigation.

Lactobacillus fermentum KP101 fermentation broth improves high-fat diet-induced hyperlipidemia in mice by modulation of liver lipid metabolism and intestinal flora dysbiosis

Abstract Non-alcoholic fatty liver disease (NAFLD) is a primary chronic liver ailment around the world, posing a significant threat to human health. Probiotics, living microorganisms that enhance intestinal flora equilibrium and mitigate blood lipid levels. This study aimed to identify probiotics with excellent antioxidant capacity from naturally fermented foods, and investigate their potential mechanisms in relieving high-fat diet (HFD)-induced liver injury and modulating intestinal flora balance. These findings fundamentally benefit the advancement of functional probiotic foods. Lactobacillus fermentum KP101, isolated from kimchi, was evaluated for its antioxidant activity. Assessment of HFD-induced liver injury was based on the biochemical markers, protein expression levels, and liver histopathology. L. fermentum KP101 remarkably reduced mice serum and liver levels of TC, TG, LDL, ALT, and AST. L. fermentum KP101 intervention effectively modulated HFD-induced dyslipidemia and activated the AMPK signalling pathway to alleviate liver injury. Specifically, the protein expression levels of SREBP-1 and p-ACC presented an obvious reduction, while the expression of p-AMPK and PPARα was notably increased following L. fermentum KP101 treatment. Moreover, L. fermentum KP101 effectively mitigated intestinal flora dysbiosis in HFD-fed mice. In summary, L. fermentum KP101 demonstrated efficacy in improving hyperlipidemia and liver metabolic disorders in mice with HFD-induced conditions.

Type 2 Diabetes and Hypertension as Risk Factors for Advanced Fibrosis in Biopsy Proven Metabolic Dysfunction-Associated Steatotic Liver Disease.

To identify the diagnostic criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) related to liver fibrosis and to characterize patients with cryptogenic steatotic liver disease (SLD) (non-MASLD) among those previously diagnosed with nonalcoholic fatty liver disease (NAFLD). This multicenter retrospective study included 511 patients diagnosed with NAFLD via liver biopsy, and the prevalence of MASLD was assessed based on the diagnostic criteria. Patients were divided into those who met the MASLD criteria and those who did not, and the characteristics of advanced fibrosis and associated cardiometabolic factors were evaluated. Of the 475 patients with NAFLD, 458 (96.4%) met the criteria for MASLD, showing a high overlap between classical NAFLD and MASLD populations. Severe fibrosis was observed, regardless of the number of cardiometabolic factors. Hypertension and diabetes mellitus significantly contributed to advanced fibrosis (≥ F3), with odds ratio of 1.92 and 2.00 (95% confidence interval of 1.17-3.16 and 1.22-3.28, respectively; both p < 0.01) on multivariate analysis. The other seventeen (3.6%) patients did not meet the diagnostic criteria for MASLD. Among them, seven had significant fibrosis and a high fibrosis-4 index. Diabetes mellitus and hypertension are key metabolic factors associated with advanced fibrosis. Some cases, classified as cryptogenic SLD, also exhibit significant fibrosis. Consequently, identifying high-risk patients, including those undergoing noninvasive tests for fibrosis, is crucial.