Non-alcoholic Fatty Liver Disease Patients Research Articles

Association of systemic inflammatory indices with anthropometric measures, metabolic factors, and liver function in non-alcoholic fatty liver disease

The present cross-sectional study aimed to explore the relationship between systemic inflammatory indices (SIIs) and anthropometric measures, metabolic, and liver function biomarkers in patients with non-alcoholic fatty liver disease (NAFLD). This study was carried out on 238 NAFLD patients with overweight or obesity, aged 18–55 years. Anthropometric measurements were done and body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were estimated. Metabolic factors including serum glucose, lipid profile, liver function biomarkers, and complete blood cell count were assessed after a 24-h fasting state. SIIs including the ratios of neutrophil to lymphocyte (NLR), monocytes to lymphocyte (MLR), platelet to lymphocyte (PLR), and monocytes to high-density lipoprotein cholesterol (MHR) were calculated. Results indicate that apart from PLR, all of the SIIs significantly changed by increasing steatosis severity (all p < 0.05). Moreover, changes in NLR showed a significant association with anthropometric indices including waist circumference (p = 0.032), BMI (p = 0.047), and WHtR (p = 0.002), as well as levels of fasting blood sugar (p = 0.045), triglycerides, (p = 0.025) and low-density lipoprotein cholesterol (p = 0.006). The findings also indicate the relations between lipid profile and all studied SIIs, notably MHR and MLR. All of the SIIs exhibited associations with some liver function indices as well. MHR was positively correlated with the metabolic risk factors of NAFLD while, oppositely, PLR was considered as a preventive marker of NAFLD.

Coprococcus protects against high-fat diet-induced nonalcoholic fatty liver disease in mice.

The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing annually, leading to substantial medical and health burdens. Numerous studies have demonstrated the potential effectiveness of intestinal probiotics as a treatment strategy for NAFLD. Therefore, the objective of this study is to identify a probiotic for the treatment of NAFLD. In this study, blood and fecal samples were collected from 41 healthy volunteers and 44 patients diagnosed with NAFLD. Analysis of the 16S rDNA sequencing data and quantitative real-time PCR (RT-qPCR) revealed a significant reduction in the abundance of Coprococcus in NAFLD patients. Subsequent animal experiments demonstrated that Coprococcus was able to effectively reverse liver lipid accumulation, inflammation, and fibrosis induced by a high-fat diet (HFD) in mice. This study provides the first in vivo evidence that Coprococcus is a beneficial bacterium capable of preventing NAFLD and has the same probiotic effect in mice as Lactobacillus GG (LGG), a positive control. Therefore, Coprococcus has the potential to serve as a probiotic for the prevention and treatment of NAFLD in humans.

Anthocyanins as Adjuvant Treatment for Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Recent studies suggest a role for anthocyanins in the treatment of non-alcoholic fatty liver disease (NAFLD). The purpose of the present review was to assess the effect of anthocyanins as an adjuvant treatment in patients with NAFLD. The literature search was conducted on MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), the Web of Science, and Scopus without language or time limits up to March 27, 2024. The primary outcomes included the severity of liver fibrosis and the level of liver transaminases. Secondary outcomes included obesity and lipid profile assessments. Standardized mean differences (SMDs) with 95% CIs were calculated for numerical outcomes. Five studies were included. The pooled effect sizes showed lower levels of liver fibrosis and liver transaminases in the anthocyanin group, but the difference was nonsignificant and small in size. The same result was obtained with anthropometric measurements of total cholesterol, low-density lipoprotein, and serum triglycerides, where effect sizes ranged from negligible to medium in magnitude but were all nonsignificant. The anthocyanin group showed a significantly lower body fat percentage (SMD = -0.41 (95%CI: -0.76; -0.06), P = 0.021). Currently, no evidence is available on the efficacy of anthocyanins in improving liver fibrosis or dyslipidemia in patients with NAFLD. There is limited evidence that anthocyanins can lower body fat percentages, but the effect was not reflected in the pooled results of other obesity indices. The few available clinical trials showed several limitations and variations regarding the doses of anthocyanins. Future clinical trials should avoid the limitations of the current studies and provide evidence supporting or refuting the use of anthocyanins in NAFLD patients.

WED-554 Lean and non-lean non-alcoholic fatty liver disease patients differ significantly with regard to gut microbiota expression: results of an observational study

WED-554 Lean and non-lean non-alcoholic fatty liver disease patients differ significantly with regard to gut microbiota expression: results of an observational study

Different aspects of immunological profile in patients with Non-Alcoholic Fatty liver disease.

NAFLD is thought to affect approximately one-fourth of the world's population. Therefore, we evaluated the role of serum complement and immunoglobulins in the NAFLD pathogenesis. 200 participants were used in this study, divided into two groups; Group I: 100 NAFLD patients and Group II: 100 healthy volunteers. The diagnosis of NAFLD is based on non-invasive methods, following the EASL guideline 2022. IgG, IgM, IgA, C3, and C4 assays were performed on all participants. When the immunological profiles of patients with NAFLD and healthy controls were compared, it was found that the mean IgA in NAFLD patients was (4.20±5.07), whereas the mean IgA in healthy controls was (2.22±1.05) (P=0.000). Additionally, a significant increase in IgG was found in NAFLD patients (17.08±3.87) compared with healthy controls (11.59±3.34), with a P value of (p<0.001). complement C3 and complement C4 levels significantly increased in nonalcoholic fatty liver disease patients (1.28± 0.61 and 0.40 ± 0.19, respectively), compared to healthy controls (0.90 ±0.27 and 0.30 ±0.12, respectively), with a significant P value (p<0.001 for each). Elevated IgA, IgG, C3 and C4 exist in patients with NAFLD and could be associated with fatty liver development and progression of hepatic fibrosis in patients with NAFLD.

Survey of physicians' knowledge about pediatric nonalcoholic fatty liver disease in China.

To evaluate physicians' awareness and knowledge towards pediatric nonalcoholic fatty liver disease (NAFLD) and their attitude toward change in nomenclature from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) in China. The questionnaire survey contained five parts (characteristics of the participants, epidemiology, diagnosis, management of NAFLD, and attitudes toward the nomenclature of MAFLD/MASLD). The participants included 53 hepatologists, 88 gastroenterologists (GEs), 74 endocrinologists (ENDOs), 61 primary care physicians (PCPs), and 157 pediatricians across 31 municipalities, provinces and autonomous regions of China's mainland. Hepatologists saw the largest number of pediatric NAFLD patients annually (median 9 [range 1-20]), with the lowest number by PCPs (even notwithstanding one patient annually). The primary sources of pediatric NAFLD knowledge were acquired via guidelines. Hepatologists had the highest total knowledge score among all five types of physicians. Approximately one-third of nonspecialists (ENDOs and PCPs) considered liver biopsy necessary for pediatric NAFLD patients, and this percentage increased to half in specialists (hepatologists and GEs). For nonspecialists, the major barriers to the management of pediatric NAFLD were poor patient adherence to lifestyle modifications and lacking confidence in managing NAFLD. Above 90% physicians agreed to change the nomenclature NAFLD to MAFLD; however, they were not sure whether it could reduce the economic burden. Despite the epidemic of pediatric NAFLD in China, a significant knowledge gap remains in the identification, diagnosis, and treatment of pediatric NAFLD, particularly among frontline workers such as pediatricians and PCPs. More education programs should be carried out in the future.

To compare the HOMA-IR and metabolic profile in lean and obese subjects with non-alcoholic fatty liver disease

Background and objectiveNon-alcoholic fatty liver disease (NAFLD) is primarily perceived as a condition prevalent among obese individuals. Its pathogenesis is closely intertwined with metabolic syndrome components. However, the association between insulin resistance and NAFLD in nonobese individuals remains ambiguous. Observational studies have scrutinized the prevalence of insulin resistance and metabolic syndrome in lean NAFLD patients.Materials and methodsThis is an observational study, and NAFLD screening was carried out among inpatient and outpatient attendees at SRM Medical College’s General Medicine Department. Out of 200 screened patients meeting inclusion and exclusion criteria, 80 were diagnosed with non-alcoholic fatty liver disease (NAFLD). The assessment of metabolic syndrome was performed using the NCEP-ATP III criteria, allowing for comparison between groups concerning insulin resistance and metabolic parameters.ResultsAmong NAFLD patients, those in the obese age group exhibited a higher prevalence of hypertension (57.8%; p < 0.001) and metabolic syndrome (75.6%; p < 0.0001). The lean NAFLD group showed elevated HOMA-IR levels (4.16) compared to obese NAFLD patients (2.92), with a significant statistical disparity (p < 0.0001). Additionally, the HSI value significantly increased in obese NAFLD patients (p < 0.00001).ConclusionInsulin resistance, a key factor in metabolic syndrome, is prevalent in lean individuals with non-alcoholic fatty liver disease (NAFLD), playing a pivotal role in its development. This resistance, linked to metabolic syndrome, promotes hepatic triglyceride and fatty acid accumulation, leading to NAFLD. Moreover, insulin resistance correlates significantly with weight gain in NAFLD patients.

The influence of acute lifestyle changes on NAFLD evolution in a multicentre cohort: a matter of body composition.

Unhealthy lifestyles represent a key element fueling Non-alcoholic fatty liver disease (NAFLD) onset and worsening. We aimed to evaluate the effects of forced acute lifestyle changes on NAFLD evolution. 187 NAFLD patients were followed two years pre- and two years during the lockdown social restrictions in three Italian medical centers. For each patient, biochemical, clinical, non-invasive liver fibrosis, nutritional, and body composition data were collected. An increase in fats and carbohydrate intake associated with impaired weekly physical activity during the lockdown was demonstrated as well as an increase in body mass index and waist-hip-ratio (p < 0.0001 for all). Total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance, and transaminases worsened during the lockdown (glucose: p = 0.0007; p < 0.0001 for the others). Moreover, NAFLD fibrosis score, liver stiffness, and controlled attenuation parameter were also impaired during the same period (p < 0.0001 for all). The bioelectrical impedance analysis (BIA) evidenced an increase of fat mass (FM), and a reduction of free fat mass (FFM) and body cell mass (BCM) (p < 0.0001 for all). The lockdown overall hepatocellular carcinoma (HCC) and Milan-out HCC occurrence revealed Hazard Ratio (HR): 2.398, 95% Confidence Interval (CI):1.16-5, p = 0.02, and HR:5.931, CI:2-17.6, p = 0.008 respectively. A liver disease stage and comorbidities independent association between both the assessed outcomes and body composition analysis in terms of mean values and variation (T1-T2 Δ) was demonstrated. The acute lifestyle changes impacted NAFLD evolution via body composition modifications negatively influencing the HCC occurrence.

Non-alcoholic fatty liver disease in patients with atrial fibrillation: a report from a global federated health network

Abstract Background Few data are available on the clinical course of patients with Atrial Fibrillation (AF) and Nonalcoholic Fatty Liver Disease (NAFLD). Purpose To evaluate the 1-year risk of all-cause death, thromboembolic events, and bleeding in AF patients with NAFLD. Methods Retrospective cohort study within the global TriNetX platform. Patients with AF were categorized into two groups: i) AF with NAFLD and ii) AF without liver diseases. The primary outcomes were the 1-year risks of a composite outcome of i) all-cause death and thrombotic events (all-cause death, acute myocardial infarction, ischemic stroke, systemic arterial thromboembolism, deep vein thrombosis, and pulmonary embolism), and hemorrhagic outcome (intracranial hemorrhage and gastrointestinal bleeding). Secondary outcomes were each component of the composite primary outcomes. Cox regression analysis before and after propensity-score-matching (PSM) was used to estimate HR and 95% confidence interval (95%CI). Sensitivity analyses were done to investigate the risk associated with cirrhosis and type of oral anticoagulant. Results We identified 22,636 AF patients with NAFLD (69±12 years, 46.7% females) and 391,014 AF patients without NAFLD (72±12 years, 42.7% females). Before PSM, AF patients with NAFLD were younger, and with a higher prevalence of cardiovascular risk factors than those without liver disease. After PSM, no difference was found between the two groups, but NAFLD patients showed a higher 1-year risk of thrombotic (HR 1.54, 95%CI 1.47-1.61) and hemorrhagic (HR 1.56, 95%CI 1.42-1.72) composite outcomes (Figure 1). The higher risk in NAFLD was consistent also for all the secondary outcomes (Figure 1). On the sensitivity analyses (Figure 2), a progressively increased risk of thrombotic and hemorrhagic events was found in non-cirrhotic and cirrhotic patients compared to patients without liver diseases, whereas non-vitamin-k antagonist (NOAC) seems to be safer and more effective than warfarin. Conclusion In AF patients, NAFLD is associated with a higher 1-year risk of all-cause death, thrombotic and hemorrhagic events. Further studies are needed to establish the best clinical approach to manage NAFLD in AF patients.Figure 1Figure 2

Role of serum endotoxin, FGF19, TLR2, TNF-α, IL-12 and IL-10 in NAFLD-associated T2DM pathogenesis: Insights into Th1 bias and protective mechanisms.

Non-alcoholic fatty liver disease (NAFLD) in non-obese patients is pathophysiologically distinct, exhibiting common immunological link with type-2 diabetes mellitus (T2DM). This study aims to delineate the role of Toll-like receptor 2 (TLR2)-mediated immuno-modulation along with its association with fibroblast growth factor receptor 4 (FGFR4) and its ligand fibroblast growth factor 19 (FGF19) in the pathogenesis of NAFLD without or with T2DM. Blood samples were collected from patients with NAFLD (n = 90), NAFLD with T2DM (n = 90) and healthy cohorts (n = 90) with consent and clinical records. Real-time polymerase chain reaction (PCR), enzyme-linked immunoassay (ELIZA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to analyze messenger ribonucleic acid (mRNA), protein expression and gene polymorphism. The molecular genetic analysis revealed the prevalence of variant allele(A) in FGFR4 gene in both cases compared to controls. The mRNA expression of FGF19 and TLR2 exhibited significant upregulation in NAFLD without T2DM compared to NAFLD with T2DM. Tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) showed upregulation in both disease cohorts compared to control while IL-10 showed significant downregulation in NAFLD with T2DM compared to the other two cohorts. Correlation analysis between FGF19 and TLR2 revealed significant positive association in both NAFLD with and without T2DM. The Th1:Th2 ratio showed significant upregulation in NAFLD with T2DM compared to NAFLD without T2DM. In conclusion, elevated serum endotoxin levels appear to contribute to NAFLD and T2DM development. Upregulated FGF19 seems to be protective against developing T2DM in NAFLD patients. Higher TLR2, TNF-α and IL-12 expression in NAFLD without T2DM suggests a Th1 bias in its pathogenesis, while reduced IL-10 in NAFLD with T2DM implies a more skewed Th1 state in this condition.

The Evolution in Non-Alcoholic Fatty Liver Disease Patients' Profile and the Associated Sustainable Challenges: A Multidisciplinary Perspective.

The prevalence and incidence of NAFLD is rising due to the obesity pandemic, caused by the widespread availability of ultra-processed foods and the decrease of physical activity. Factors such as socioeconomic status (SES), ethnicity and geographical location are associated with NAFLD, with lower SES correlating with higher incidence, particularly in regions like America or Europe. Beside the quality of food, the quantity also plays a crucial role. The World Health Organization (WHO) recommends a Mediterranean diet with a balanced energy intake. Since no hard medical treatment is available for NAFLD, lifestyle adjustments are key. Patient empowerment by providing relevant information and co-ownership of the therapy will increase the implementation rate and enhance the quality of medical follow-up and medication adherence, as studies report a good adherence to medication among patients who are well-aware of the severity of their disease. Regarding sustainability, patients with NAFLD have a high load of ambulatory follow-up, which, since the COVID-19 pandemic, can be partially provided by teleconsulting. Both patients' lifestyle modifications and healthcare practitioners' therapeutical strategy can decrease the carbon footprint.

Dose finding for ZSP1601 in patients with nonalcoholic steatohepatitis using population pharmacokinetics and exposure–response approach

IntroductionZSP1601 is a novel pan-phosphodiesterase inhibitor developed in China specifically for the treatment of nonalcoholic fatty liver disease (NAFLD). AimThe aim is to develop a population pharmacokinetic (pop PK) model for ZSP1601 by integrating data from two clinical studies. This undertaking aims to deepen our understanding of the clinical factors that influence ZSP1601 exposure while simultaneously investigating exposure–response (ER) relationships related to efficacy and safety. The goal is to guide formulating optimal dosage strategies in the subsequent phases of clinical trials. MethodsAnalysis of pooled concentration–time data from 95 subjects, with 2647 observations from two clinical trials involving healthy volunteers and NAFLD patients, employed a nonlinear mixed-effects modeling approach to characterize ZSP1601 pharmacokinetics. Covariate impact on ZSP1601 pharmacokinetics was investigated, and relationships between ZSP1601 exposure, efficacy and safety endpoints were explored. ResultsA two-compartment model featuring sequential zero-order then first-order absorption and first-order elimination effectively described ZSP1601′s pharmacokinetic profile. Covariate analyses identified body weight as a statistically significant factor affecting drug central volume, while FED (food consumption) influenced absorption rate constant and duration. The Sigmoid Emax model aptly captured exposure–response relationships for ALT (alanine aminotransferase), AST (aspartate aminotransferase), and LFC (liver fat content) percentage changes relative to baseline and ZSP1601 exposure levels (AUCss) on the 29th day. ZSP1601 exposure levels (Cmax1) exhibited a significant exposure–response relationship with headaches (p < 0.001). ConclusionThe PopPK model and ER analysis, based on available data, comprehensively characterizes ZSP1601′s pharmacokinetic, safety and efficacy profile, aiding informed decisions regarding dosage selection for the drug's complete developmental trajectory. The exposure-response (ER) analysis yields quantitative insights into the optimal balance of efficacy and safety within different dosage regimens for patient administration. In light of these findings, the dose regimen of 100 mg administered twice daily is proposed for subsequent clinical investigations.

Assessing the Utility of Acoustic Radiation Force Impulse in the Evaluation of Non-Alcoholic Fatty Liver Disease with Severe Obesity or Steatosis.

Non-alcoholic fatty liver disease (NAFLD) encompasses a heterogeneous spectrum ranging from simple steatosis to fibrosis and cirrhosis. Fibrosis, associated with long-term overall mortality and liver-related events, requires evaluation. Traditionally, liver biopsy has been the gold standard for diagnosing fibrosis. However, its invasive nature, potential complications, and sampling variability limit widespread use. Consequently, various non-invasive tests have been developed as alternatives for diagnosing fibrosis in NAFLD patients. This study aimed to compare the accuracy of non-invasive tests (NITs) and evaluate the diagnostic accuracy of acoustic radiation force impulse (ARFI), one of the point shear wave techniques, compared to conventional methods, assessing its effective role in diagnosis. This is a retrospective study; a total of 136 patients diagnosed with fatty liver disease through ultrasonography were enrolled. The anthropometric data of the patients were collected on the day of admission and blood tests, measurements of ARFI, and a point shear test were conducted using abdominal ultrasound; a biopsy was performed the following day. In addition, we calculated the aspartate aminotransferase-to-platelet ratio index (APRI) index based on four factors (FIB-4) and the NAFLD fibrosis score (NFS). Subsequently, we assessed the diagnostic accuracy of NITs within various subgroups based on the extent of obesity, steatosis, or NAFLD activity score. ARFI has been shown to have the highest diagnostic value among various NITs, with AUROC values of 0.832, 0.794, 0.767, and 0.696 for ARFI, APRI, FIB-4, and NFS, respectively. In the morbidly obese subgroup, the AUROC values of ARFI, APRI, FIB-4, and NFS were 0.805, 0.769, 0.736, and 0.674. In the group with severe steatosis or non-alcoholic steatohepatitis (NASH), the AUROC values were 0.679, 0.596, 0.661, and 0.612, respectively, for severe steatosis and 0.789, 0.696, 0.751, and 0.691, respectively, for NASH. In conclusion, ARFI is not affected by various factors and maintains diagnostic accuracy compared to serum NITs. Therefore, we can recommend ARFI as a valuable diagnostic test to screen for advanced fibrosis in patients with NAFLD.

Association between severity of nonalcoholic fatty liver disease and major adverse cardiovascular events in patients assessed by coronary computed tomography angiography

BackgroundThe effect of nonalcoholic fatty liver disease (NAFLD) on major adverse cardiovascular events (MACEs) can be influenced by the degree of coronary artery stenosis. However, the association between the severity of NAFLD and MACEs in patients who underwent coronary computed tomography angiography (CCTA) is unclear.MethodsA total of 341 NAFLD patients who underwent CCTA were enrolled. The severity of NAFLD was divided into mild NAFLD and moderate-severe NAFLD by abdominal CT results. The degree of coronary artery stenosis was evaluated by using Coronary Artery Disease Reporting and Data System (CAD-RADS) category. Cox regression analysis and Kaplan–Meier analysis were used to assess poor prognosis.ResultsDuring the follow-up period, 45 of 341 NAFLD patients (13.20%) who underwent CCTA occurred MACEs. The severity of NAFLD (hazard ratio [HR] = 2.95[1.54–5.66]; p = 0.001) and CAD-RADS categories 3–5 (HR = 16.31[6.34–41.92]; p < 0.001) were independent risk factors for MACEs. The Kaplan–Meier analysis showed that moderate to severe NAFLD patients had a worsen prognosis than mild NAFLD patients (log-rank p < 0.001). Moreover, the combined receiver operating characteristic curve of the severity of NAFLD and CAD-RADS category showed a good predicting performance for the risk of MACEs, with an area under the curve of 0.849 (95% CI = 0.786–0.911).ConclusionThe severity of NAFLD was independent risk factor for MACEs in patients with obstructive CAD, having CAD-RADS 3–5 categories on CCTA.

Hypogonadism and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), recently proposed to be renamed to metabolic dysfunction-associated steatotic liver disease (MASLD), is a major global public health concern, affecting approximately 25-30% of the adult population and possibly leading to cirrhosis, hepatocellular carcinoma, and liver transplantation. The liver is involved in the actions of sex steroids via their hepatic metabolism and production of the sex hormone-binding globulin (SHBG). Liver disease, including NAFLD, is associated with reproductive dysfunction in men and women, and the prevalence of NAFLD in patients with hypogonadism is considerable. A wide spectrum of possible pathophysiological mechanisms linking NAFLD and male/female hypogonadism has been investigated. As therapies targeting NAFLD may impact hypogonadism in men and women, and vice versa, treatments of the latter may affect NAFLD, and an insight into their pathophysiological pathways is imperative. This paper aims to elucidate the complex association between NAFLD and hypogonadism in men and women and discuss the therapeutic options and their impact on both conditions.

Berberine directly targets AKR1B10 protein to modulate lipid and glucose metabolism disorders in NAFLD

Ethnopharmacological relevanceBerberine (BBR) is the main active component from Coptidis rhizome, a well-known Chinese herbal medicine used for metabolic diseases, especially diabetes for thousands of years. BBR has been reported to cure various metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD). However, the direct proteomic targets and underlying molecular mechanism of BBR against NAFLD remain less understood. Aim of the studyTo investigate the direct target and corresponding molecular mechanism of BBR on NAFLD is the aim of the current study. Materials and methodsHigh-fat diet (HFD)-fed mice and oleic acid (OA) stimulated HepG2 cells were utilized to verify the beneficial impacts of BBR on glycolipid metabolism profiles. The click chemistry in proteomics, DARTS, CETSA, SPR and fluorescence co-localization analysis were conducted to identify the targets of BBR for NAFLD. RNA-seq and shRNA/siRNA were used to investigate the downstream pathways of the target. ResultsBBR improved hepatic steatosis, ameliorated insulin resistance, and reduced TG levels in the NAFLD models. Importantly, Aldo-keto reductase 1B10 (AKR1B10) was first proved as the target of BBR for NAFLD. The gene expression of AKR1B10 increased significantly in the NAFLD patients' liver tissue. We further demonstrated that HFD and OA increased AKR1B10 expression in the C57BL/6 mice's liver and HepG2 cells, respectively, whereas BBR decreased the expression and activities of AKR1B10. Moreover, the knockdown of AKR1B10 by applying shRNA/siRNA profoundly impacted the beneficial effects on the pathogenesis of NAFLD by BBR. Meanwhile, the changes in various proteins (ACC1, CPT-1, GLUT2, etc.) are responsible for hepatic lipogenesis, fatty acid oxidation, glucose uptake, etc. by BBR were reversed by the knockdown of AKR1B10. Additionally, RNA-seq was used to identify the downstream pathway of AKR1B10 by examining the gene expression of liver tissues from HFD-fed mice. Our findings revealed that BBR markedly increased the protein levels of PPARα while downregulating the expression of PPARγ. However, various proteins of PPAR signaling pathways remained unaffected post the knockdown of AKR1B10. ConclusionsBBR alleviated NAFLD via mediating PPAR signaling pathways through targeting AKR1B10. This study proved that AKR1B10 is a novel target of BBR for NAFLD treatment and helps to find new targets for the treatment of NAFLD by using active natural compounds isolated from traditional herbal medicines as the probe.

Gut Microbiota Profile Changes in Patients with Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease: A Metagenomic Study.

Gut microbiota imbalances have a significant role in the pathogenesis of Inflammatory Bowel Disease (IBD) and Non-Alcoholic Fatty Liver Disease (NAFLD). Herein, we compared gut microbial composition in patients diagnosed with either IBD or NAFLD or a combination of both. Seventy-four participants were stratified into four groups: IBD-NAFLD, IBD-only, NAFLD-only patients, and healthy controls (CTRLs). The 16S rRNA was sequenced by Next-Generation Sequencing. Bioinformatics and statistical analysis were performed. Bacterial α-diversity showed a significant lower value when the IBD-only group was compared to the other groups and particularly against the IBD-NAFLD group. β-diversity also showed a significant difference among groups. The higher Bacteroidetes/Firmicutes ratio was found only when comparing IBD groups and CTRLs. Comparing the IBD-only group with the IBD-NAFLD group, a decrease in differential abundance of Subdoligranulum, Parabacteroides, and Fusicatenibacter was found. Comparing the NAFLD-only with the IBD-NAFLD groups, there was a higher abundance of Alistipes, Odoribacter, Sutterella, and Lachnospira. An inverse relationship in the comparison between the IBD-only group and the other groups was shown. For the first time, the singularity of the gut microbial composition in IBD and NAFLD patients has been shown, implying a potential microbial signature mainly influenced by gut inflammation.

The effects of grape seed extract supplementation on cardiovascular risk factors, liver enzymes and hepatic steatosis in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study.

Despite the high antioxidant potential of grape seed extract (GSE), very limited studies have investigated its effect on non-alcoholic fatty liver disease (NAFLD). Therefore, this study was conducted with the aim of investigating the effect of GSE on metabolic factors, blood pressure and steatosis severity in patients with NAFLD. In this double-blind randomized clinical trial study, 50 NAFLD patients were divided into two groups of 25 participants who were treated with 520mg/day of GSE or the placebo group for 2 months. The parameters of glycemic, lipid profile, blood pressure and steatohepatitis were measured before and after the intervention. The GSE group had an average age of 43.52 ± 8.12 years with 15 women and 10 men, while the placebo group had an average age of 44.88 ± 10.14 years with 11 women and 14 men. After 2 months of intervention with GSE, it was observed that insulin, HOMA-IR, TC, TG, LDL-c, ALT, AST, AST/ALT, SBP, DBP and MAP decreased and QUICKi and HDL-c increased significantly (p-value for all < 0.05). Also, before and after adjustment based on baseline, the average changes indicated that the levels of insulin, HOMA-IR, TC, TG, LDL-c, SBP, DBP, MAP in the GSE group decreased more than in the control group (p for all < 0.05). Furthermore, the changes in HDL-c were significantly higher in the GSE group (p < 0.05). The between-groups analysis showed a significant decrease in the HOMA-β and AST before and after adjustment based on baseline levels (p < 0.05). Moreover, the changes in QUICKi after adjustment based on baseline levels were higher in the GSE group than in the control group. Also, between-groups analysis showed that the severity of hepatic steatosis was reduced in the intervention group compared to the placebo group (P = 0.002). It seems that GSE can be considered one of the appropriate strategies for controlling insulin resistance, hyperlipidemia, hypertension and hepatic steatosis in NAFLD patients. The clinical trial was registered in the Iranian Clinical Trial Registration Center (IRCT20190731044392N1). https://irct.behdasht.gov.ir/trial/61413 . (The registration date: 30/03/2022).

Current Management of Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of other causes of liver fat accumulation. The prevalence of NAFLD is increasing and now among top causes of hepatocellular carcinoma. The diagnosis of NAFLD requires evidence from liver biopsy. There are currently no specific drugs for therapy of NAFLD. Current mainstay for management of NAFLD is lifestyle interventions focused around weight loss. Lifestyle interventions can be done by dietary modification or increasing physical activity level. Pioglitazone and vitamin E are only recommended for patient whom was confirmed NAFLD by liver biopsy. New agents such as obeticholic acid, elafibranor, selonsertib, and cenicriviroc are still waiting for phase III result to be recommended as therapy for NAFLD. Bariatric surgery can be advised for NAFLD patient with obesity who is not adequately controlled by medical therapy.

Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) presents as a common liver disease characterized by an indistinct pathogenesis. Disulfidptosis is a recently identified mode of cell death. This study aimed to investigate the potential role of disulfidptosis-related genes (DRGs) in the pathogenesis of NAFLD. Gene expression profiles were obtained from the bulk RNA dataset GSE126848 and the single-cell RNA dataset GSE136103, both associated with NAFLD. Our study assessed the expression of DRGs in NAFLD and normal tissues. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify the key NAFLD-specific differentially expressed DRGs (DE-DRGs). To explore the biological functions and immune regulatory roles of these key DE-DRGs, we conducted immune infiltration analysis, functional enrichment analysis, consensus clustering analysis, and single-cell differential state analysis. Finally, we validated the expression and biological functions of DRGs in NAFLD patients using histology and RNA-sequencing transcriptomic assays with human liver tissue samples. Through the intersection of WGCNA, differentially expressed genes, and DRGs, two key DE-DRGs (DSTN and MYL6) were identified. Immune infiltration analysis indicated a higher proportion of macrophages, T cells, and resting dendritic cells in NAFLD compared to control liver samples. Based on the key DE-DRGs, Two disulfidptosis clusters were defined in GSE126848. Cluster 1, with higher expression of the key DE-DRGs, exhibited increased immune infiltration abundance and was closely associated with oxidative stress and immune regulation compared to cluster 2. High-resolution analysis of mononuclear phagocytes highlighted the potential role of MYL6 in intrahepatic M1 phenotype Kupffer cells in NAFLD patients. Our transcriptome data revealed that the expression levels of the majority of DRGs were significantly increased in NAFLD patients. NAFLD patients exhibit elevated MYL6 correlating with inflammation, oxidative stress, and disease severity, offering promising diagnostic specificity. This comprehensive study provides evidence for the association between NAFLD and disulfidptosis, identifying potential target genes and pathways in NAFLD. The identification of MYL6 as a possible treatment target for NAFLD provided a novel understanding of the disease's development.