Non-alcoholic Fatty Liver Disease Patients Research Articles

Prognostic value of metabolic dysfunction-associated steatotic liver disease over coronary computed tomography angiography findings: comparison with no-alcoholic fatty liver disease

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is the proposed name change for non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the association of cardiovascular disease risk with MASLD and NAFLD in patients who underwent clinically indicated coronary computed tomography angiography (CCTA).MethodsThis retrospective study included 2289 patients (60% men; mean age: 68 years) with no history of coronary artery disease who underwent CCTA. The steatotic liver was defined as a hepatic-to-spleen attenuation ratio of < 1.0 on CT just before CCTA. MASLD is defined as the presence of hepatic steatosis along with at least one of the five cardiometabolic risk factors. Adverse CCTA findings were defined as obstructive and/or high-risk plaques. Major adverse cardiac events (MACE) encompassed composite coronary events, including cardiovascular death, acute coronary syndrome, and late coronary revascularization.ResultsMASLD and NAFLD were identified in 415 (18%) and 368 (16%) patients, respectively. Adverse CCTA findings were observed in 40% and 38% of the patients with MASLD and with NAFLD, respectively. Adverse CCTA findings were significantly associated with MASLD (p = 0.007) but not NAFLD (p = 0.253). During a median follow-up of 4.4 years, 102 (4.4%) MACE were observed. MASLD was significantly associated with MACE (hazard ratio 1.82, 95% CI 1.18–2.83, p = 0.007), while its association with NAFLD was not significant (p = 0.070). By incorporating MASLD into a prediction model of MACE, including the risk score and adverse CCTA findings, global chi-squared values significantly increased from 87.0 to 94.1 (p = 0.008).ConclusionsPatients with MASLD are likely to have a higher risk of cardiovascular disease than those with NAFLD. Concurrent assessment of MASLD during CCTA improves the identification of patients at a higher risk of cardiovascular disease among those with clinically indicated CCTA.

Low ankle–brachial index is associated with higher cardiovascular mortality in individuals with nonalcoholic fatty liver disease

Background and aimsAnkle brachial index (ABI) is a risk factor for cardiovascular mortality, but it is unclear whether ABI is associated with cardiovascular mortality in patients with nonalcoholic fatty liver disease (NAFLD). The current study aimed to evaluate the association between ABI with cardiovascular and all-cause mortality in patients with NAFLD.MethodsWe performed a cohort study using the data of the1999–2004 National Health and Nutrition Examination Survey data of adults. Mortality data were followed up to December 2015. NAFLD was defined by the hepatic steatosis index or the US fatty liver index. ABI was classified into three groups: ABI ≤ 0.9 (low value); 0.9 < ABI ≤ 1.1 (borderline value); ABI greater than 1.1 (normal value).ResultsWe found that low ABI was associated with an increased risk of cardiovascular mortality in patients with NAFLD (HR: 2.42, 95% CI 1.10–5.33 for low value ABI vs normal value ABI, P for trend = 0.04), and the relationship was linearly and negatively correlated in the range of ABI < 1.4. However, low ABI was not associated with all-cause mortality in patients with NAFLD. Stratified by cardiovascular disease, ABI remains inversely correlated with cardiovascular mortality in NAFLD patients without cardiovascular disease. Stratified by diabetes, ABI is inversely correlated with cardiovascular mortality in NAFLD patients regardless of diabetes status.ConclusionsLow ABI is independently associated with higher cardiovascular mortality in NAFLD cases. This correlation remains significant even in the absence of pre-existing cardiovascular disease or diabetes.

Associations between estimated glucose disposal rate and arterial stiffness and mortality among US adults with non-alcoholic fatty liver disease

BackgroundThe estimated glucose disposal rate (eGDR), an effective indicator of insulin resistance, has been related to acute coronary syndrome, ischemic stroke and heart failure. This study aims to explore the relationship between eGDR and arterial stiffness, all-cause mortality and cardiovascular mortality in patients with non-alcoholic fatty liver disease (NAFLD).MethodsParticipants with NAFLD were chosen from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. The main outcomes are arterial stiffness (represented by estimated pulse wave velocity, ePWV), all-cause and cardiovascular mortality. Multiple cox regression models, restricted cubic spline, sensitivity analysis and subgroup analysis were carried out to investigate the correlation between the insulin resistance indicators and mortality and arterial stiffness. Furthermore, receiver operating characteristic curves were used to compare the predictive value of the eGDR with the triglyceride-glucose (TyG) index and the homeostasis model assessment of insulin resistance (HOMA-IR) for all-cause and cardiovascular mortality.ResultsIn this study, a total of 4,861 participants were included for analysis. After adjusting confounding factors in the multivariate weighted cox regression model, the eGDR was inversely associated with the all-cause mortality (Q4 vs. Q1, HR =0.65 (0.48-0.89, P=0.01) and cardiovascular mortality (Q4 vs. Q1, HR =0.35 (0.19-0.65, P&amp;lt;0.001). Compared with TyG index and HOMA-IR, the eGDR shows excellent predictive value in all-cause mortality (0.588 vs. 0.550 vs. 0.513, P &amp;lt; 0.001) and cardiovascular mortality (0.625 vs. 0.553 vs. 0.537, P &amp;lt; 0.001). In addition, we found a significant negative correlation between eGDR and arterial stiffness (β=-0.13(-0.14–0.11, P&amp;lt; 0.001). However, TyG index and HOMA-IR showed no significant correlation to arterial stiffness.ConclusionsLow eGDR (an indicator of insulin resistance) levels are related to an increased risk of arterial stiffness and mortality in NAFLD patients in the United States.

AN ASSOCIATION OF METABOLIC SYNDROME WITH NONALCOHOLIC FATTY LIVER DISEASE

Objectives: Nonalcoholic fatty liver disease is strongly linked with hepatic fatty infiltration and visceral adiposity, therefore, being a cause and a result of metabolic syndrome. The objective of the study is to find an association of metabolic syndrome (MetS) with nonalcoholic fatty liver disease (NAFLD). Methods: A total of 342 subjects from which 86 NAFLD 86 control were suitably selected for study duration of 1 year. Diagnosis of nonalcoholic fatty liver disease was done by liver imaging and based on liver enzymes. MetS assessment was done by the national cholesterol education program adult treatment panel III (NCEP ATP III) criteria. Estimation of all biochemical and hematological parameters and liver enzymes was done following standard guidelines. Mean comparison of quantitative data in different groups was analyzed with one-way analysis of variance. Results: There were significant high levels of body mass index, waist circumference, and lipid profiles in NAFLD patients in comparison to control population (p&lt;0.001). According to the NCEP ATP III criteria, 59.3% of NAFLD were present with MetS where risk estimate was significant (odds ratio=2.15). Conclusion: This study suggests that there is an increased in all the components of MetS and gross changes in biochemical markers in cases of NAFLD. Therefore, whenever MetS factors are met in the clinical checkups, patients must be diagnosed for NAFLD by imaging (fatty liver).

Impact of nomenclature as metabolic associated steatotic liver disease on steatotic liver disease prevalence and screening: a prospective population survey in Asians.

The introduction of the latest nomenclature, metabolic associated steatotic liver disease (MASLD), proposed by the multi-society without Asian society consensus statement, aims to redefine the diagnostic criteria for metabolic associated fatty liver disease (MAFLD). However, its effect on the epidemiology in Asia remains unclear. We conducted a population-based cross-sectional survey on fatty liver disease using multistage stratified random sampling of participants from Guangzhou, a representative area in China (ChiCTR2000033376). Demographic, socioeconomic, lifestyle, and laboratory data were collected. Hepatic steatosis and the severity of fibrosis were assessed using FibroScan. A total of 7388 individuals were recruited, the proportion of which meeting the definitions for nonalcoholic fatty liver disease (NAFLD), MAFLD, and MASLD were 2359 (31.9%), 2666 (36.1%), and 2240 (30.3%), respectively. One hundred and twenty (1.6%) patients had cryptogenic SLD, and 537 (7.3%) patients were diagnosed with MetALD. MASLD did not significantly differ from NAFLD and MAFLD, except that MAFLD patients had a lower proportion of males, hypertension, and diabetes and were less likely to consume tea (P<0.05). Both cryptogenic SLD and MASLD non-MAFLD patients exhibited milder hepatic steatosis and a lower frequency of liver injury than NAFLD, MAFLD, or MASLD patients (all P<0.05). An increased HOMA-IR (adjusted OR: 1.33, 95% CI: 1.10-2.03) was associated with higher risk of moderate-to-severe steatosis for MASLD non-MAFLD patients, while consuming more cups of tea (P for trend=0.015) showed inverse associations. Irrespective of terminology used is that fatty liver disease is highly prevalent in the Han Chinese population. Differences in insulin resistance and lifestyle risk factors are associated with redefinition disparities.

Exploration and Validation of Ferroptosis-Associated Genes in ADAR1 Deletion-Induced NAFLD through RNA-seq Analysis

BackgroundFerroptosis, characterized by excessive iron ions and lipid peroxides accumulation, contributes to Nonalcoholic Fatty Liver Disease (NAFLD) development. The role of ADAR1, crucial for lipid metabolism and immune regulation, in ferroptosis-related NAFLD remains unexplored. MethodsIn this study, we analyzed the expression of ADAR1 in NAFLD patients using the GSE66676 database. Subsequently, We investigated the effects of ADAR1 knockdown on mitochondrial membrane potential (MMP), Fe2+ levels, oxidation products, and ferroptosis in NAFLD cells through in vitro and in vivo experiments. Additionally, RNA-seq analysis was performed following ADAR1 depletion in an NAFLD cell model. Overlapping and ferroptosis-related genes were identified using a Venn diagram, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted as well. Furthermore, a protein-protein interaction (PPI) network was constructed to identify hub genes associated with ferroptosis. ResultsWe found the expression level of ADAR1 was downregulated in NAFLD patients and 22 ferroptosis-associated genes were differentially expressed in a NAFLD cell model upon ADAR1 knockdown. Based on PPI network, we identified NOS2, PTGS2, NOX4, ALB, IL6, and CCL5 as the central genes related to ferroptosis. ADAR1 deletion-related NAFLD was found to be involved in the ferroptosis signaling pathway. NOS2, PTGS2, ALB, and IL6 can serve as potential biomarkers. These findings offer new insights and expanded targets for NAFLD prevention and treatment. ConclusionThese findings provide new strategies and potential targets for preventing and treating NAFLD. NOS2, PTGS2, ALB, and IL6 may serve as biomarkers for ADAR1 deletion-related NAFLD, which could help for developing its new diagnostic and therapeutic strategies.

Can modulation of gut microbiota affect anthropometric indices in patients with non-alcoholic fatty liver disease? An umbrella meta-analysis of randomized controlled trials.

Modulating the gut microbiota population by administration of probiotics, prebiotics, and synbiotics has shown to have a variety of health benefits in different populations, particularly those with metabolic disorders. Although the promising effects of these compounds have been observed in the management of patients with non-alcoholic fatty liver disease (NAFLD), the exact effects and the mechanisms of action are yet to be understood. In the present study, we aimed to evaluate how gut microbiota modulation affects anthropometric indices of NAFLD patients to achieve a comprehensive summary of current evidence-based knowledge. Two researchers independently searched international databases, including PubMed, Scopus, and Web of Science, from inception to June 2023. Meta-analysis studies that evaluated the effects of probiotics, prebiotics, and synbiotics on patients with NAFLD were entered into our umbrella review. The data regarding anthropometric indices, including body mass index, weight, waist circumference (WC), and waist-to-hip ratio (WHR), were extracted by the investigators. The authors used random effect model for conducting the meta-analysis. Subgroup analysis and sensitivity analysis were also performed. A total number of 13 studies were finally included in our study. Based on the final results, BMI was significantly decreased in NAFLD patients by modulation of gut microbiota [effect size (ES): -0.18, 05% CI: -0.25, -0.11, P<0.001]; however, no significant alteration was observed in weight and WC (ES: -1.72, 05% CI: -3.48, 0.03, P=0.055, and ES: -0.24, 05% CI: -0.75, 0.26, P=0.353, respectively). The results of subgroup analysis showed probiotics had the most substantial effect on decreasing BMI (ES: -0.77, 95% CI: -1.16, -0.38, P<0.001) followed by prebiotics (ES: -0.51, 95% CI: -0.76, -0.27, P<0.001) and synbiotics (ES: -0.12, 95% CI: -0.20, -0.04, P=0.001). In conclusion, the present umbrella meta-analysis showed that although modulation of gut microbiota by administration of probiotics, prebiotics, and synbiotics had promising effects on BMI, no significant change was observed in the WC and weight of the patients. No sufficient data were available for other anthropometric indices including waist-to-hip ratio and waist-to-height ratio and future meta-analyses should be done in this regard.

Anthropometry, Laboratory, and PNPLA3 Polymorphisms in a Novel Model for Early identification and Evaluation of Nonalcoholic Fatty Liver Disease.

BackgroundSome anthropometric, laboratory, and genetic variations, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) genetic variants, have been associated with nonalcoholic fatty liver disease (NAFLD). Liver biopsy is the most accurate NAFLD diagnostic method, but it is invasive; hence, noninvasive diagnostics are required for the early diagnosis and assessment of NAFLD. Patient and MethodsThis prospective case-control study included 107 NAFLD patients and 107 healthy controls. All individuals underwent anthropometric measurements, abdominal ultrasonography, laboratory tests, and evaluation for PNPLA3 polymorphisms. ResultsPatients with NAFLD had higher levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) than healthy individuals (p = 0.03, p < 0.0001). Additionally, patients with NAFLD had substantially lower albumin (P = 0.01) and leptin (P < 0.0001) levels than healthy individuals. BMI leptin and CRP levels were independent indicators of NAFLD severity (p = 0.05–0.004). GG is the most prevalent genotype in patients with moderate to severe NAFLD. A novel model based on four markers (leptin, CRP, BMI, and PNPLA3 polymorphism) was developed. The AUC values for distinguishing between the healthy subjects and those with varying degrees of NAFLD severity (mild, moderate, and severe) were 0.99, 0.99, and 1.0, respectively. ConclusionAnthropometric measurements, such as BMI and laboratory results, including liver enzymes, CRP, inflammatory markers, lipid parameters, and genetic markers, especially PNPLA3 polymorphisms, can provide an accurate, sensitive, and specific noninvasive approach for the early identification and assessment of NAFLD and can guide its management. This may minimize the need for liver biopsy to assess NAFLD. Further large-scale studies are needed to confirm these findings and verify the model in larger studies.

Correlation between Serum Levels of Nitric Oxide and Adropin and Erectile Dysfunction in Males with Nonalcoholic Fatty Liver Disease: An Observational Study.

The current study aimed to evaluate the serum levels of nitric oxide (NO) and adropin in males with non-alcoholic fatty liver disease (NAFLD) induced erectile dysfunction (ED) and NAFLD patients without ED and controls. The current study selected 165 participants from the hepatology department from November 2021 to November 2022. The patients were either suffering from NAFLD with normal liver functions or non-alcoholic steatohepatitis with abnormal liver functions. They were diagnosed by abdominal ultrasonography. Participants were evaluated using the validated Arabic version of the International Index of Erectile Function (ArIIEF-5), the Arabic form of the Generalized Anxiety Disorder-7 (GAD-7) questionnaire and the Patient Health Questionnaire-9 (PHQ-9). Noteworthy, there were significant positive correlations between ArIIEF-5 score, NO, adropin and total testosterone (r = 0.380, p = 0.001; r = 0.507, p =  < 0.001; r = 0.246, p = 0.038, respectively). Meanwhile, there were significant negative correlations between ArIIEF-5 score, creatinine, duration of the disease and scores of GAD-7 and PHQ-9 (r = -0.656, p =  < 0.001; r = -0.368, p = 0.002; r = -0.663, p =  < 0.001; r = -0.248, p = 0.037, respectively). Finally, a linear regression analysis revealed that GAD-7, creatinine, and adropin were the only strong independent predictors of ArIIEF-5, as the 95% confidence interval in the form of upper and lower bounds was -0.349, -0.843, p < 0.001, -6.507, -18.402, p < 0.001, 0.476, 0.117, and p 0.002, respectively. Impaired NO and adropin levels play a potential role in the development of ED in patients with NAFLD.

Supplementation of Micro- and Macronutrients-A Role of Nutritional Status in Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a condition in which the pathological cumulation of fat with coexisting inflammation and damage of hepatic cells leads to progressive dysfunctions of the liver. Except for the commonly well-known major causes of NAFLD such as obesity, dyslipidemia, insulin resistance, or diabetes, an unbalanced diet and imbalanced nutritional status should also be taken into consideration. In this narrative review, we summarized the current knowledge regarding the micro- and macronutrient status of patients suffering from NAFLD considering various diets and supplementation of chosen supplements. We aimed to summarize the knowledge indicating which nutritional impairments may be associated with the onset and progression of NAFLD at the same time evaluating the potential therapy targets that could facilitate the healing process. Except for the above-mentioned objectives, one of the most important aspects of this review was to highlight the possible strategies for taking care of NAFLD patients taking into account the challenges and opportunities associated with the micronutrient status of the patients. The current research indicates that a supplementation of chosen vitamins (e.g., vitamin A, B complex, C, or D) as well as chosen elements such as zinc may alleviate the symptoms of NAFLD. However, there is still a lack of sufficient data regarding healthy ranges of dosages; thus, further research is of high importance in this matter.

MiR-18 regulates lipid metabolism of non-alcoholic fatty liver disease via IGF1.

We aimed to illustrate the regulatory effect of miR-18 on the onset of non-alcoholic fatty liver disease (NAFLD). MiR-18 level in liver tissues collected from NAFLD patients and mice was detected. In vivo and in vitro influences of miR-18 on biochemical indexes, glucose tolerance and insulin resistance (IR) in NAFLD were determined. H&E staining was conducted to observe hepatic steatosis in NAFLD mice. The downstream target of miR-18 was finally detected by luciferase assay. MiR-18 was upregulated in liver tissues collected from NAFLD patients and mice. Knockdown of miR-18 reduced levels of AST, ALT, TG and TC in NAFLD mice and culture medium of FFA-induced LO2 cells. Meanwhile, knockdown of miR-18 alleviated hepatic steatosis and IR in NAFLD mice. IGF1 was the target of miR-18, and it was negatively regulated by miR-18. MiR-18 is upregulated in NAFLD patients and mice. Knockdown of miR-18 alleviates HFD-induced hepatic steatosis and IR through interacting with IGF1 to regulate to lipid metabolism and insulin signals.

DGAT2 Plays a Crucial Role to Control ESRRAPROX1 Transcriptional Network to Maintain Hepatic Mitochondrial Sustainability.

Diacylglycerol O-acyltransferase 2 (DGAT2) synthesizes triacylglycerol (TG) from diacylglycerol; therefore, DGAT2 is considered as a therapeutic target for steatosis. However, the consequence of inhibiting DGAT2 is not fully investigated due to side effects including lethality and lipotoxicity. In this article, we observed the role of DGAT2 in hepatocarcinoma. The role of DGAT2 is analyzed via loss-of-function assay. DGAT2 knockdown (KD) and inhibitor treatment on HepG2 cell line was analyzed. Cumulative analysis of cell metabolism with bioinformatic data were assessed, and further compared with different cohorts of liver cancer patients and non-alcoholic fatty liver disease (NAFLD) patients to elucidate how DGAT2 is regulating cancer metabolism. Mitochondrial function is suppressed in DGAT2 KD HepG2 cell along with the decreased lipid droplets. In the aspect of the cancer, DGAT2 KD upregulates cell proliferation. Analyzing transcriptome of NAFLD and hepatocellular carcinoma (HCC) patients highlights negatively correlating expression patterns of 73 lipid-associated genes including DGAT2. Cancer patients with the lower DGAT2 expression face lower survival rate. DGAT2 KD cell and patients' transcriptome show downregulation in estrogen- related receptor alpha (ESRRA) via integrated system for motif activity response analysis (ISMARA), with increased dimerization with corepressor prospero homeobox 1 (PROX1). DGAT2 sustains the stability of mitochondria in hepatoma via suppressing ESRRA-PROX1 transcriptional network and hinders HCC from shifting towards glycolytic metabolism, which lowers cell proliferation.

Clinical predictive value of control attenuation parameters in combination with miR-192-5p in patients with acute pancreatitis in nonalcoholic fatty liver disease.

Control attenuation parameters (CAP) can detect nonalcoholic fatty liver disease (NAFLD). Our previous study found that miR-192-5p could screen for acute pancreatitis (AP) in NAFLD patients. This study focused on the role of CAP and miR-192-5p in NAFLD of acute AP. AP patients and controls were enrolled. Classification of AP patients into NAFLD/AP patients and non-NAFLD/AP was made based on the CAP value. CAP was measured by liver transient elastography. Serum miR-192-5p was measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Logistic regression analysis was conducted to examine the risk factors for the development of NAFLD. Receiver operating characteristic (ROC) was assessed for the predictive value of AP severity. NAFLD was more common in the AP group than in the controls (35.00% vs. 8.75%). The CAP value was higher in AP patients with NAFLD than in non-NAFLD, whereas miR-192-5p was significantly lower in AP patients with NAFLD. Additionally, AP patients with NALFD are more likely to experience respiratory failure, systemic inflammatory response syndrome (SIRS), and pancreatic necrosis with longer hospitalisation and exacerbate the incidence of moderate to severe AP. Both miR-192-5p and TG are potential risk factors for the development of NAFLD in patients with AP. Furthermore, the CAP value gradually increased with increasing AP severity, while miR-192-5p gradually decreased. Finally, the sensitivity and specificity of CAP combined with miR-192-5p for the prediction of moderate to severe AP were scored as 82.61% and 82.43%, respectively. NAFLD exacerbated the progression of AP, and CAP combined with miR-192-5p could predict the severity of AP. Our study may provide more reference for AP disease progression and treatment.

Prevalence and outcome of sarcopenia in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of conditions, progressing from mild steatosis to advanced fibrosis. Sarcopenia, characterized by decreased muscle strength and mass, shares common pathophysiological traits with NAFLD. An association exists between sarcopenia and increased NAFLD prevalence. However, data on the prevalence of sarcopenia in NAFLD and its impact on the outcomes of NAFLD remain inconsistent. To analyze the prevalence and outcomes of sarcopenia in patients with NAFLD. We conducted a comprehensive search for relevant studies in MEDLINE, Embase, and Scopus from their inception to June 2023. We included studies that focused on patients with NAFLD, reported the prevalence of sarcopenia as the primary outcome, and examined secondary outcomes, such as liver fibrosis and other adverse events. We also used the Newcastle-Ottawa scale for quality assessment. Of the 29 studies included, the prevalence of sarcopenia in NAFLD varied widely (1.6% to 63.0%), with 20 studies reporting a prevalence of more than 10.0%. Substantial heterogeneity was noted in the measurement modalities for sarcopenia. Sarcopenia was associated with a higher risk of advanced fibrosis (odd ratio: 1.97, 95% confidence interval: 1.44-2.70). Increased odds were consistently observed in fibrosis assessment through biopsy, NAFLD fibrosis score/body mass index, aspartate aminotransferase to alanine aminotransferase ratio, diabetes (BARD) score, and transient elastography, whereas the fibrosis-4 score showed no such association. Sarcopenia in NAFLD was associated with a higher risk of steatohepatitis, insulin resistance, cardiovascular risks, and mortality. This systematic review highlights the critical need for standardized diagnostic criteria and measurement methods for sarcopenia in NAFLD patients. The variability in study designs and assessment methods for sarcopenia and liver fibrosis may account for the inconsistent findings. This review demonstrates the multidimensional impact of sarcopenia on NAFLD, indicating its importance beyond liver-related events to include cardiovascular risks, mortality, and metabolic complications.

The Role of PNPLA3_rs738409 Gene Variant, Lifestyle Factors, and Bioactive Compounds in Nonalcoholic Fatty Liver Disease: A Population-Based and Molecular Approach towards Healthy Nutrition.

This study aimed to investigate the impact of a common non-synonymous gene variant (C>G, rs738409) in patatin-like phospholipase domain-containing 3 (PNPLA3), leading to the substitution of isoleucine with methionine at position 148 (PNPLA3-I148M), on susceptibility to nonalcoholic fatty liver disease (NAFLD) and explore potential therapeutic nutritional strategies targeting PNPLA3. It contributed to understanding sustainable dietary practices for managing NAFLD, recently referred to as metabolic-dysfunction-associated fatty liver. NAFLD had been diagnosed by ultrasound in a metropolitan hospital-based cohort comprising 58,701 middle-aged and older Korean individuals, identifying 2089 NAFLD patients. The interaction between PNPLA3 and lifestyle factors was investigated. In silico analyses, including virtual screening, molecular docking, and molecular dynamics simulations, were conducted to identify bioactive compounds from foods targeting PNPLA3(I148M). Subsequent cellular experiments involved treating oleic acid (OA)-exposed HepG2 cells with selected bioactive compounds, both in the absence and presence of compound C (AMPK inhibitor), targeting PNPLA3 expression. Carriers of the risk allele PNPLA3_rs738409G showed an increased association with NAFLD risk, particularly with adherence to a plant-based diet, avoidance of a Western-style diet, and smoking. Delphinidin 3-caffeoyl-glucoside, pyranocyanin A, delta-viniferin, kaempferol-7-glucoside, and petunidin 3-rutinoside emerged as potential binders to the active site residues of PNPLA3, exhibiting a reduction in binding energy. These compounds demonstrated a dose-dependent reduction in intracellular triglyceride and lipid peroxide levels in HepG2 cells, while pretreatment with compound C showed the opposite trend. Kaempferol-7-glucoside and petunidin-3-rutinoside showed potential as inhibitors of PNPLA3 expression by enhancing AMPK activity, ultimately reducing intrahepatic lipogenesis. In conclusion, there is potential for plant-based diets and specific bioactive compounds to promote sustainable dietary practices to mitigate NAFLD risk, especially in individuals with genetic predispositions.

Impact of Adherence to the Mediterranean Diet on Antioxidant Status and Metabolic Parameters in NAFLD Patients: A 24-Month Lifestyle Intervention Study.

The Mediterranean Diet (MedDiet) is recognized as a healthy dietary pattern. Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of fat in the liver. To assess the antioxidant status in erythrocytes, plasma, and peripheral blood mononuclear cells (PBMCs) of NAFLD patients following a 24-month lifestyle intervention based on the MedDiet. Adult patients (n = 40; aged 40-60 years) diagnosed with NAFLD by magnetic resonance imaging were divided into two groups based on their adherence to the MedDiet. Consumption was assessed using a validated 143-item semiquantitative Food Frequency Questionnaire. Anthropometrics, biochemistry parameters, intrahepatic fat contents (IFC), antioxidants, and inflammatory biomarkers were measured in plasma and erythrocytes before and after the intervention. After the intervention, body mass index (BMI) and plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-chol), triglycerides, malondialdehyde (MDA), and cytokeratin-18 (CK18) decreased, and high-density lipoprotein cholesterol (HDL-chol) increased. Participants with high adherence to MedDiet showed lower IFC, hepatic enzyme (AST, ALT, and GGT), glycemia, oxidase LDL (oxLDL) plasma levels, and erythrocyte MDA levels. Higher antioxidant activity (erythrocyte catalase-CAT, superoxide dismutase-SOD, glutathione peroxidase-GPx, glutathione reductase-GRd, and total glutathione-GSH as well as PBMCs-CAT gene expression) was observed in these patients, along with a reduction of PBMCs reactive oxygen species production and Toll-like receptor 4 (TLR4) expression. Inverse associations were observed between adherence to the MedDiet and BMI, glycemia, AST, IFC, and CK18 plasma levels and oxLDL, CAT, SOD, and GRd activities in erythrocytes. A significant linear regression was observed between adherence to the MedDiet and antioxidant score. Adherence to the MedDiet is associated with improved plasma and PBMC antioxidant and inflammatory biomarker profiles and high antioxidant defences in erythrocytes.

Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

The efficacy of multi-disciplinary lifestyle modifications in Taiwanese nonalcoholic steatohepatitis patients.

Lifestyle modification is the standard of care for nonalcoholic fatty liver disease (NAFLD) patients. We aimed to investigate the efficacy of a short-term lifestyle modification program in the disease course of Taiwanese nonalcoholic steatohepatitis (NASH) patients with paired biopsies. All patients received a 6-month, strict multidisciplinary program of lifestyle modifications led by physicians, dieticians, and nursing staff. The histopathological and clinical features were assessed. The endpoints were normalization of transaminase levels, metabolic parameters, a decrease in the NAFLD activity score (NAS) ≥1, and a decrease in the fibrosis stage ≥1. We also aimed to elucidate the predictors associated with disease progression. A total of 37 patients with biopsy-proven NASH were enrolled. The normalization of transaminase levels increased from 0% to 13.5%. There were also significantly increased proportions of patients with normal total cholesterol, triglyceride, and hemoglobin A1c levels. Fifteen (40.5%) patients had an increased NAS ≥1, whereas 10 (27.0%) patients had NAS regression. Twelve (32.4%) patients had increased fibrosis ≥1 stage. Only 2 (5.4%) patients experienced fibrosis regression. A high fasting plasma glucose (FPG) level was associated with NAS progression. Older age and higher transaminase and FPG levels were factors associated with fibrosis progression. Seven (18.9%) patients achieved a body weight reduction >3%, and 4 (57.1%) of them experienced NAS regression. No significant effect of weight reduction on the progression of fibrosis was observed. The short-term lifestyle modification program significantly decreased liver enzymes and metabolic parameters in NASH patients. A more precise or intensive program may be needed for fibrosis improvement.

Neutrophil to albumin ratio: a biomarker in non-alcoholic fatty liver disease and with liver fibrosis.

Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) and its potential to progress to liver fibrosis, it is crucial to identify the presence of NAFLD in patients to guide their subsequent management. However, the current availability of non-invasive biomarkers for NAFLD remains limited. Therefore, further investigation is needed to identify and develop non-invasive biomarkers for NAFLD. A retrospective analysis was conducted on 11,883 patients admitted to the Healthcare Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2016 to December 2019 and divided into NAFLD and non-NAFLD groups. Anthropometric and laboratory examination data were collected. The correlations between variables and NAFLD were evaluated using the student's t-test or Mann-Whitney U test and binary logistic regression analysis. The predictive ability of these variables for NAFLD was assessed using the areas under the curves (AUCs) of receiver operating characteristics. Among the included patients, 3,872 (32.58%) were diagnosed with NAFLD, with 386 (9.97%) individuals having liver fibrosis. Patients with NAFLD exhibited a higher proportion of males, elevated body mass index (BMI), and increased likelihood of hypertension, diabetes mellitus, and atherosclerosis. Logistic regression analysis identified the neutrophil to albumin ratio (NAR) as the most promising novel inflammation biomarkers, with the highest AUC value of 0.701, a cut-off value of 0.797, sensitivity of 69.40%, and specificity of 66.00% in identifying the risk of NAFLD. Moreover, NAR demonstrated superior predictive value in identifying NAFLD patients at risk of liver fibrosis, with an AUC value of 0.795, sensitivity of 71.30%, and specificity of 73.60% when NAR reached 1.285. These findings highlight that the novel inflammatory biomarker, NAR, is a convenient and easily accessible non-invasive predictor for NAFLD and NAFLD with liver fibrosis.

L-Ornithine-l-Aspartate (LOLA) Normalizes Metabolic Parameters in Models of Steatosis, Insulin Resistance and Metabolic Syndrome.

l-Ornithine- l-aspartate (LOLA) reduces toxic ammonium (NH3) plasma levels in hepatic encephalopathy. NH3 detoxification/excretion is achieved by its incorporation into urea and glutamine via activation of carbamoyl phosphate synthetase 1 (CSP1) by l-ornithine and stimulation of arginase by l-aspartate. We aimed at identifying additional molecular targets of LOLA as a potential treatment option for non-alcoholic fatty liver disease (NAFLD). In primary hepatocytes from NAFLD patients, urea cycle enzymes CSP1 and ornithine transcarbamylase (OTC) increase, while the catabolism of branched-chain amino acids (BCAAs) decreases with disease severity. In contrast, LOLA increased the expression rates of the BCAA enzyme transcripts bcat2, bckdha, and bckdk. In untreated HepG2 hepatoblastoma cells and HepG2-based models of steatosis, insulin resistance, and metabolic syndrome (the latter for the first time established herein), LOLA reduced the release of NH3; beneficially modulated the expression of genes related to fatty acid import/transport (cd36, cpt1), synthesis (fasn, scd1, ACC1), and regulation (srbf1); reduced cellular ATP and acetyl-CoA; and favorably modulated the expression of master regulators/genes of energy balance/mitochondrial biogenesis (AMPK-α, pgc1α). Moreover, LOLA reconstituted the depolarized mitochondrial membrane potential, while retaining mitochondrial integrity and avoiding induction of superoxide production. Most effects were concentration-dependent at ≤40 mM LOLA. We demonstrate for l-ornithine-l-aspartate a broad range of reconstituting effects on metabolic carriers and targets of catabolism/energy metabolism impaired in NAFLD. These findings strongly advocate further investigations to establish LOLA as a safe, efficacious, and cost-effective basic medication for preventing and/or alleviating NAFLD.