Nonalcoholic Fatty Liver Disease Research Articles

Modern aspects of therapy of metabolic associated liver disease in patients with type 2 diabetes mellitus

Metabolic associated fatty liver disease (MAFLD) is currently the most common liver disease. The main risk factors for its development are poor nutrition, sedentary lifestyle and obesity. MAFLD is associated with various cardiometabolic conditions – lipid metabolism disorders, cardiovascular pathology and carbohydrate metabolism disorders. The association of MAFLD and type 2 diabetes mellitus (DM) is common among patients, since these diseases have a common pathogenesis link – insulin resistance. The combination of these diseases has a mutual negative effect on each other and increases the risks of cardiovascular diseases, hospitalizations, as well as the risks of liver fibrosis progression. Therefore, the detection of MAFLD and its treatment in type 2 DM are extremely important to improve the patient’s prognosis. Diagnostics of MAFLD includes laboratory and instrumental research methods. The “gold standard” of diagnostics is considered to be liver biopsy, but due to the fact that this method is invasive, it is rarely used and only for differential diagnostics of MAFLD with other liver pathologies. The most accessible instrumental method for detecting liver steatosis is ultrasound. Treatment of MAFLD primarily involves lifestyle changes (rational nutrition with limitation of simple carbohydrates and animal fats, adequate physical activity) and weight loss. Also, hypoglycemic drugs used to treat type 2 diabetes (metformin, pioglitazone, glucagon-like peptide-1 agonists) can have a certain positive effect on MAFLD. Essential phospholipids, which have membrane-stabilizing, antioxidant and antifibrotic effects, are also an important component of MAFLD treatment. A number of domestic and foreign studies have shown the high efficiency of Essential Phospholipids both in relation to biochemical parameters in patients with a combination of type 2 diabetes and MAFLD, and in relation to ultrasound signs, improving the function and structure of the liver in MAFLD, as well as slowing the progression of liver fibrosis.

Association between menopause, body composition, and nonalcoholic fatty liver disease: A prospective cohort in northern China

BackgroundThe association between menopause, changes in body composition, and nonalcoholic fatty liver disease is not clear, and there is a lack of weight management strategies for perimenopausal women from the perspective of preventing nonalcoholic fatty liver disease. MethodsA total of 1316 postmenopausal and 3049 premenopausal women in the Kailuan cohort in China between 2006 and 2017 were enrolled and followed up till 2021. Cox regression models, including the causal mediation analyses, were used to estimate the association between menopause and nonalcoholic fatty liver disease and the potential mediation effect of changes in body composition. We also explored the impact of weight changes on the correlation between menopause and nonalcoholic fatty liver disease. ResultsWomen who experienced menopause had a higher risk of nonalcoholic fatty liver disease than premenopausal women (9-year cumulative incidence: 56.87 % vs. 48.80 %, adjusted hazard ratio = 1.219, 95 % confidence interval: 1.088–1.365). The nine-year cumulative incidence of nonalcoholic fatty liver disease was higher among overweight/obese postmenopausal women (67.24 % vs. 45.74 %, P < 0.001) and those with abdominal obesity (63.36 % vs. 49.69 %, P < 0.001); however, the hazard ratio of menopause for nonalcoholic fatty liver disease was more evident in women with a body mass index under 23.0 kg/m2 (hazard ratio = 1.434, 95 % confidence interval: 1.168–1.759) and those with normal waist circumference (hazard ratio = 1.362, 95 % confidence interval: 1.129–1.643), which could partially be explained by the visceral fat index (7.09 % and 7.35 % mediation, respectively). Weight loss of 3 % or more or reduction in waist circumference by 5 % or more was associated with a 31.1 % reduction (95 % confidence interval, 20.8 %–40.0 %) or a 14.2 % reduction (95 % confidence interval, 1.1 %–25.6 %) in the risk of nonalcoholic fatty liver disease among the premenopausal women. For postmenopausal women, weight gain of 3 % or more was associated with an increased risk of nonalcoholic fatty liver disease, especially in individuals with a body mass index under 23.0 kg/m2. ConclusionMenopause was associated with a higher risk of nonalcoholic fatty liver disease, partially by increasing visceral fat. Controlling weight in perimenopausal women may reduce the risk.

Exosomes Derived from Diabetic Microenvironment-Preconditioned Mesenchymal Stem Cells Ameliorate Nonalcoholic Fatty Liver Disease and Inhibit Pyroptosis of Hepatocytes

AimPyroptosis, a type of programmed cell death, is a key mechanism underlying non-alcoholic fatty liver disease (NAFLD). Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exos) have the potential to ameliorate NAFLD, an effect that is enhanced by curcumin preconditioning. We previously reported that diabetic microenvironment preconditioning enhances the secretion capacity and anti-inflammatory activity of MSCs. Therefore, we hypothesized that MSC-Exos would inhibit hepatocyte pyroptosis and thereby ameliorate NAFLD, and that diabetic microenvironment preconditioning would enhance these effects. MethodsMSCs were preconditioned in a diabetic microenvironment (pMSCs). MSC-Exos and pMSC-Exos collected from MSCs or pMSCs were applied to methionine- and choline-deficient (MCD)-induced NAFLD mice and in vitro models involving induction with lipopolysaccharide or palmitic acid to mimic hepatic steatosis and injury. MCC950 treatment was used as a positive control. We analyzed the characteristics of NAFLD and pyroptosis markers. Protein profiles of MSC-Exos and pMSC-Exos were evaluated by label-free quantitative proteomics. ResultsIn vivo, MSC-Exos partially attenuated inflammation and fibrosis, but not lipid deposition and NAFLD progression in the livers of NAFLD mice. pMSC-Exos significantly improved lipid metabolism, hepatic steatosis, inflammation, and fibrosis but also retarded the progression of NAFLD. Pyroptosis was upregulated in the liver of NAFLD mice. MSC-Exos and pMSC-Exos inhibited pyroptosis, and the effect of the latter was greater than that of the former. In vitro, MSC-Exos and pMSC-Exos ameliorated hepatocyte steatosis, lipid metabolism disorder, and inflammation, and pMSC-Exos exerted a greater inhibitory effect on hepatocyte pyroptosis than MSC-Exos did, which were remitted after inhibition of peroxiredoxin-1 (PRDX-1). ConclusionMSC-Exos ameliorated NAFLD and inhibited hepatocyte pyroptosis by downregulating the NLRP3/Caspase-1/GSDMD pathway, effects enhanced by pMSC-Exos, partly due to PRDX-1 upregulation.

Gallstones increase the risk of nonalcoholic fatty liver: A case-control study.

Nonalcoholic fatty liver disease (NAFLD) and gallstones are generally seen together, and many of the risk factors for fatty liver and gallstones are common and similar. Therefore, this study aims to investigate the relationship between NAFLD and gallstones. This case-control study was conducted in patients referred to Imam Khomeini and Golestan hospitals of Ahvaz University of Medical Sciences in 2023, whose ultrasound showed fatty liver. Patients who were diagnosed with NAFLD by ultrasound were considered as the case group, and patients who did not have diagnostic findings of fatty liver in ultrasound were considered as the control group. Finally, the information recorded in the checklists was statistically analyzed using SPSS version 26 (SPSS Inc.). Three hundred patients were included in our study, 150 as cases and 150 as controls. There was no significant difference between the groups in terms of gender and age (gender P-value: 0.817/age P-value: 0.102). A statistically significant relationship was found between obesity, diabetes mellitus (DM), the presence of gallstones, and NAFLD (weight p-value < 0.001/DM p-value < 0.001/gallstones P-value: 0.03). In addition, based on binary logistic regression analysis, the presence of gallstones increases the odds of NAFLD by 2.33 times (P-value: 0.035). Furthermore, having DM and increasing each BMI unit increases the odds of NAFLD by 16 times and 30%, respectively (BMI p-value < 0.001/DM p-value < 0.001). Based on the results of our study, gallstones are an important risk factor for NAFLD. The possible mechanisms are the existence of common risk factors between gallstones and NAFLD and the reduction of motility and flow of bile in the bile ducts with the presence of gallstones.

Potential Mechanism of Perillaldehyde in the Treatment of Nonalcoholic Fatty Liver Disease Based on Network Pharmacology and Molecular Docking

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic metabolic liver diseases worldwide. Perillaldehyde (4-propyl-1-en-2-ylcyclohexene-1-aldehyde, PA) is a terpenoid compound extracted from Perilla, which has effective pharmacological activities such as anti-inflammatory, antidepressant, and anticancer. This study aimed to explore the pharmacological effects of PA in intervening with NAFLD and reveal its potential mechanisms. Firstly, we identified the core targets of PA intervention therapy for NAFLD through network pharmacology and molecular docking techniques. After that, in vitro animal experiments such as H&E and Masson staining, immunofluorescence, immunohistochemistry, and western blot were conducted to validate the results network effectively pharmacology predicted. Network pharmacology analysis suggested that PPAR-α may be the core target of PA intervention in NAFLD. H&E and Masson staining showed that after low-dose (50mg/kg) PA administration, there was a noticeable improvement in fat deposition in the livers of NAFLD mice, and liver tissue fibrosis was alleviated. Immunohistochemical and immunofluorescence analysis showed that low dose (50mg/kg) PA could reduce hepatocyte apoptosis, decrease the content of pro-apoptosis protein Bax, and increase the expression of anti-apoptosis protein Bcl-2 in NAFLD mice. Western blot results confirmed that low-dose (50mg/kg) PA could increase the expression of PPAR-α and inhibit the expression of NF-κB in NAFLD mice. Our study indicated that PA could enhance the activity of PPAR-α and reduce the level of NF-κB in NAFLD mice, which may positively affect the prevention of NAFLD.

Investigation of the mechanism by which Tegillarca granosa polysaccharide regulates non-alcoholic fatty liver disease in mice by modulating Lactobacillus Johnsonii

Non-alcoholic fatty liver disease (NAFLD), a prevalent chronic liver disease, is marked by excessive lipid deposition in the liver without alcohol abuse. Scapharca subcrenatum, a major Chinese farmed bivalve, yields S. subcrenatum polysaccharide (TGP), an active substance with known biological activity. Previous studies revealed TGP's significant regulatory effect on a high-fat diet (HFD)-induced NAFLD in mice. However, the precise mechanisms, particularly involving gut microbiota, remain unclear. In the current study, an antibiotic-treated mouse model was established to determine the mechanistic role of the gut microbiota in the observed anti-obesity effects of TGP. In addition, 16S rRNA genomic and metagenome-derived taxonomic analyses were performed to assess the gut microbial populations. The results showed that TGP selectively enhanced the number of the eosinophilic bacterium Lactobacillus johnsonii, which was reduced in HFD mice. Of note, the oral administration of L. johnsonii formulations to HFD mice alleviated NAFLD, and this was related to regulating lipid metabolism and the accumulation of lipids in the liver. Therefore, the current study uncovered a potential pathway for developing NAFLD treatment strategies based on the interaction between TGP and the gut microbiota.

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

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

Helicobacter Pylori Infection Is not Associated with Nonalcoholic Fatty Liver Disease: A Two-year Cohort Study.

Previous studies reported inconsistent results of the association between Helicobacter pylori (H. pylori) infection and nonalcoholic fatty liver disease (NAFLD). A cohort study of 2063 adults without NAFLD at baseline, who participated in a repeated health check-up including a 13C urea breath test and abdominal ultrasonography, was conducted to evaluate the link between H. pylori infection and NAFLD development. During a mean follow-up period of 1.7 years, we did not found a significant association between H. pylori infection and NAFLD (Hazard ratio (HR) = 1.10 (0.86, 1.40), p = 0.4689). We also found that higher age, body mass index (BMI), systolic blood pressure (systolic BP), diastolic blood pressure (diastolic BP), fasting blood glucose, triglycerides, total cholesterol, low density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were risk factors, and high density lipoprotein cholesterol (HDL-C) was a protective factor for NAFLD development. H. pylori infection might not be positively related to NAFLD development.

Diosgenin attenuates nonalcoholic fatty liver disease through mTOR-mediated inhibition of lipid accumulation and inflammation

Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms in vitro and in vivo were examined using quantitative polymerase chain reaction and western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.

Transcription factor ETV4 plays a critical role in the development of non-alcoholic fatty liver disease

The Angiopoietin-like 4 (ANGPTL4) and ETS Variant Transcription Factor 4 (ETV4) are involved in the metabolic transition and carcinogenesis in the liver. However, the role of ETV4 in the development of non-alcoholic fatty liver disease (NAFLD) is currently unknown. Our study reveals that ETV4 expression was upregulated in the diet-induced non-alcoholic fatty liver disease, and plays a critical role in the dysregulated lipid metabolism. We demonstrate a mechanism by which ANGPTL4 regulates lipid homeostasis via involving the AMPK/ETV4 axis. Transient knockdown of ETV4 abolished the ANGPTL4-induced expression of Srebp1c, Acc and Fasn. Insulin treatment potentially increased the physical association of ETV4 with SREBP1, and promotes nuclear translocation and transcriptional activity of SREBP1. In addition, we show that combined therapy with omega-3 fatty acids and diacylglycerol O-acyltransferase inhibitor 1 (DGAT1) inhibitor (A-922500) counteracted the ANGPTL4-ETV4 axis-induced lipogenesis in vitro, and in vivo in obese mice via activation of GPR120-βarrestin2-AMPK pathway. Finally, we demonstrate that targeted pharmacologic therapy using GalNac-ETV4 siRNA that specifically inhibits ETV4 gene expression in the liver protects against diet-induced NAFLD, obesity and dyslipidemia. Hence, our study reveal previously unrecognized role of ETV4 in the NAFLD, and provides rationale targeting ETV4 to treat NAFLD.

Assessment and integration of multiparametric MRI for liver fibrosis staging in rat non-alcoholic steatohepatitis: Evaluation of diagnostic efficiency and model interpretation

ObjectivesMulti-parametric MRI techniques, including intravoxel incoherence motion (IVIM), iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL IQ), T2* mapping and T2 mapping, were employed to develop and validate a predictive model for non-alcoholic steatohepatitis (NASH) diagnosis and liver fibrosis (LF) staging in rats. The combined model was interpreted using SHapley Additive exPlanations (SHAP) values for model understanding. Materials and methods160 healthy Sprague-Dawley (SD) rats were divided into control (n = 24) and experimental (n = 136) groups, and the 12-week and 16-week groups were injected intraperitoneally with carbon tetrachloride (CCl4) for 4 weeks, one month before the final feeding period. All rats were subjected to pathological examination to determine LF stage. Upon the study’s completion, 147 SD rats were assessed for liver fibrosis. Results84 SD rats were diagnosed with NASH and 31, 10, and 43 rats were histologically diagnosed with no fibrosis (F0), early LF (F1-F2), and late LF (F3-F4). For diagnosis of NASH and staging of liver fibrosis associated with NASH, a combined multi-parameter magnetic resonance imaging prediction model has a higher area under the ROC curve (AUC) than individual diffusion parameters, especially in advanced stages of fibrosis, with an AUC of 0.929 for the combined model. In SHAP, the free fluid(FF) value contributes most to the model for diagnosing NASH and advanced liver fibrosis, while the T2 value contributes most for diagnosing liver fibrosis and the apparent diffusion coefficient (ADC) value contributes most for diagnosing liver cirrhosis. ConclusionsThe integration of several magnetic resonance imaging methods along with SHAP value analysis provides a more comprehensive and theoretical investigation into the mechanisms and factors contributing to the progression of liver fibrosis in NASH, offering insights from various angles.

Day napping and metabolic-associated fatty liver disease: A systematic review and meta-analysis of observational studies.

Napping inevitably affects human health, and the association between napping and metabolism-related diseases is being more seriously considered. However, the conclusions of studies on the relationship between napping and fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD) remain controversial. We performed a systematical search to identify eligible studies up to July 31, 2024. The fixed effects model was used to calculate the pooled odds ratio (OR). Subgroup were performed. Sensitivity analyses and meta-regression analysis were carried to explore the heterogeneity. Publication bias was assessed by funnel plot and Egger's test. 48,248 participants from 13 studies were included in this meta-analysis. The pooled analysis found napping to have an association between the incidence of NAFLD/MAFLD (OR, 1.13; 95% confidence interval (CI), 1.08-1.19; P < .001). The robustness of this study was confirmed using a sensitivity analysis. No apparent heterogeneity or publication bias was observed. Further meta-analysis revealed that short nap duration did not greatly affect the incidence of the disease (OR, 1.01; 95% CI, 0.91-1.12; P = .80). However, long nap duration was significantly linked to high risk of the disease (OR, 1.21; 95% CI, 1.02-1.44; P = .03). Patients with NAFLD/MAFLD may had higher prevalence of napping habit. Future research is warranted to conduct a dose-response analysis, measure the effects of confounding factors, and explore the causal relationships between NAFLD/MAFLD. The research protocol was registered and approved in PROSPERO (registration no: CRD42023439507).

Gegen Qinlian Decoction Modulates Atherosclerosis and Lipid Metabolism Through Cellular Interplay and Signaling Pathways.

The objective of this study is to investigate Gegen Qinlian decoction (GQD) effects on lipid metabolism and explore its mechanism for preventing and treating atherosclerosis. An atherosclerotic rat model was established, and after an 8-week high-fat diet, atherosclerosis and non-alcoholic fatty liver disease were assessed. Subsequently, GQD was administered at low and high doses. Histopathological aortic wall changes, hepatic lipid deposition, and blood lipid changes were evaluated. ELISA indicated the influence of TNF-α and IL-13, and Western blotting revealed MerTK, ABCA1, and LXR-α expression. A foam macrophage model was established, and Cell activity was detected by the MTT method. ELISA indicated the influence of PPAR-γ. The expression of ABCA1, ABCA7, ABCG1, GAS6, MerTK, SCARB1, LXR- α and LXR-β mRNA were detected by qPCR. and Western blotting revealed MerTK and LXR-α expression. The impact of drug-containing serum of GQD on efferocytosis-related factors was studied. GQD improved atherosclerosis and non-alcoholic fatty liver disease and reduced serum low-density lipoprotein levels in the high-dose group. The high- and low-dose groups showed upregulated ABCA1, MerTK, and LXR-α expression in blood vessels and the liver, respectively. GQD decreased serum TNF-α and increased IL-13 levels. PPAR-γ expression was elevated in the high-, and low-dose groups. In the high-and low-dose groups, ABCA7, GAS6, SCARB1, and LXR-α, ABCA1 and MerTK, and ABCG1 gene expression were upregulated, respectively. Both low- and high-dose serum-containing drugs promoted LXR-β gene expression, and LXR-α protein expression was improved in the high-dose group. GQD improves rat atherosclerosis and hepatic lipid metabolism by regulating PPAR-γ, LXR-α, LXR-β, ABCA1, ABCA7, and ABCG1 expression and augmenting cellular intercalation through the GAS6/TAM pathway.

Investigating the causal links between obstructive sleep apnea and gastrointestinal diseases mediated by metabolic syndrome through mendelian randomization

Previous studies have pointed to a potential link between Obstructive Sleep Apnea (OSA) and gastrointestinal diseases, suggesting that this relationship might be influenced by the presence of Metabolic Syndrome. However, the exact role of these factors in determining gastrointestinal diseases has not been thoroughly explored. In our study, we utilized data from the Genome-wide Association Studies (GWAS) database, focusing on OSA, metabolic syndrome characteristics such as Body Mass Index (BMI), waist circumference, triglycerides, cholesterol, hypertension, type 2 diabetes, and common gastrointestinal diseases including chronic gastritis, gastric ulcers, irritable bowel syndrome, colorectal cancer, inflammatory bowel disease, cholecystitis, nonalcoholic fatty liver, and dyspepsia. By applying Single-variable and Multi-variable Mendelian randomization methods, we aimed to assess the correlation between OSA and gastrointestinal diseases and investigate whether this correlation is influenced by metabolic syndrome. Our findings revealed a strong association between OSA and an increased risk of chronic gastritis, gastric ulcers, inflammatory bowel disease, and nonalcoholic fatty liver disease. No significant connections were found with irritable bowel syndrome, colorectal cancer, cholecystitis, or dyspepsia. Additionally, OSA was linked to metabolic syndrome traits like BMI, waist circumference, triglycerides, hypertension, and type 2 diabetes. Further analysis showed that BMI, triglycerides, and hypertension were causally related to inflammatory bowel disease; BMI, waist circumference, hypertension, and type 2 diabetes to nonalcoholic fatty liver disease; and triglycerides, hypertension, and type 2 diabetes to chronic gastritis. The multivariable analysis indicated that hypertension mediates the relationship between OSA and chronic gastritis; BMI, triglycerides, and hypertension mediate the link between OSA and inflammatory bowel disease; and waist circumference mediates the connection between OSA and nonalcoholic fatty liver disease. To wrap up, this finding helps us understand how these issues might be related and stresses the role of metabolic syndrome in preventing them, which could lessen their effect on health.

Heightened TPD52 linked to metabolic dysfunction and associated abnormalities in zebrafish

The tumor protein D52 (TPD52) gene encodes a proto-oncogene protein associated with various medical conditions, including breast and prostate cancers. It plays a role in multiple biological pathways such as cell growth, differentiation, and apoptosis. The function of TPD52 in lipid droplet biosynthesis has been investigated in vitro. However, its precise role in lipid metabolism in animal models is not fully understood. To investigate the functions of TPD52 in vivo, we performed a conditional TPD52 protein expression analysis using a Tet-off transgenic system to establish conditionally expressed Tpd52 transgenic zebrafish. The effect of Tpd52 on lipogenesis was assessed using various methods, including whole-mount Oil Red O staining, histological examination, and measurement of inflammatory markers and potential targets using real-time quantitative polymerase chain reaction and immunoblotting in Tpd52 fish. Zebrafish with increased Tpd52 levels exhibited notable weight gain and the enlargement of fat deposits, which were mainly attributed to an increase in the volume of adipocytes. Moreover, Tpd52 overexpression was correlated with the triggering of the adipocyte differentiation signaling pathway. During adipocytic differentiation in response to nutrient status, our observations revealed adipogenesis, nonalcoholic fatty liver disease, and metabolic cardiomyopathy (MCM) in Tpd52 transgenic zebrafish. To gain a deeper understanding of the contribution of these proteins to the regulation of cellular growth, we investigated the expression of their corresponding genes and proteins in zebrafish. In the present study, the activated protein kinase pathway was identified as the primary target of TPD52. Adult Tpd52 zebrafish showed increased lipid accumulation, resulting in the development of visceral obesity, nonalcoholic fatty liver disease, and MCM. These findings strongly suggest that TPD52 actively contributes to adipose tissue expansion and its subsequent effects. This investigation provides compelling evidence that Tpd52 facilitates adipocyte development and related metabolic comorbidities in zebrafish.

Prevalence and Correlates of Probable Nonalcoholic Steatohepatitis (NASH) in Pars Cohort Study.

Studies on the prevalence of nonalcoholic steatohepatitis (NASH) and the factors associated with its high prevalence among Iranian people are limited. This study evaluated the prevalence of NASH and its associated factors among Iranian adults using Pars Cohort Study (PCS) data. This cross-sectional study was conducted based on PCS, which includes 40-75-year-old adults from the Valashahr area. NASH was defined as alanine aminotransferase (ALT) higher than 40 U/L without evidence of hepatitis B or C infections. The prevalence of NASH and its associations with basic and demographic characteristics, socioeconomic characteristics, medical history, gastrointestinal symptoms, and laboratory tests were evaluated. Overall, 8734 patients, including 3917 men (44.8%), were enrolled in this study. The mean age of participants was 52.62 years (SD=9.68), and 605 individuals had NASH (6.9%). In the regression analysis, in contrast to female gender (OR=0.31, 95% CI=0.249‒0.386, P<0.001) and age (OR=0.951, 95% CI=0.941‒0.962, P<0.001), history of heart disease (OR=1.499, 95% CI=1.146‒1.962, P=0.003), history of diabetes (OR=1.523, 95% CI=1.162‒1.995, P=0.002), hypertension (OR=1.241, 95% CI=1.023‒1.506, P=0.029), being overweight or obese (OR=2.192, 95% CI=1.755‒2.737, P<0.001), being in the richest or second richest wealth index quantiles (OR=1.315, 95% CI=1.107‒1.156, P=0.002), and increased waist circumference (OR=1.409, 95% CI=1.107‒1.793, P<0.005) were independently associated with a higher risk of having NASH. In this study, we determined the prevalence of NASH and found male gender, younger age, history of heart disease, history of diabetes, hypertension, socioeconomic status, and obesity as possible factors associated with a higher risk of NASH among Iranians.

The methyltransferase MLL4 promotes non-alcoholic steatohepatitis by enhancing NF-κB signaling.

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem worldwide, ranging from non-alcoholic fatty liver (NAFL) to the more severe metabolic non-alcoholic steatohepatitis (NASH). Although many studies have elucidated the pathogenesis of NAFLD, the epigenetic regulatory mechanism from NAFL to NASH remains incompletely understood. The histone H3 lysine 4 methyltransferase, MLL4 (also called KMT2D), is a critical epigenetic transcriptional coactivator that mediates overnutrition-induced steatosis in mice, but its potential role in the progression of NASH remains largely unknown. Here, we show that mice lacking the one allele of the Mll4 gene are resistant to hepatic steatosis, inflammation, and fibrosis in NASH conditions compared to wild-type controls. Transcriptome analysis of the livers of control and Mll4+/- mice identified pro-inflammatory genes regulated by the nuclear factor kappa B (NF-κB) signaling pathway as major target genes of MLL4. We show that MLL4 binds to p65 and that MLL4 is required for NF-κB transactivation. Myeloid-specific Mll4 knockout mice showed an almost complete block of NASH, while hepatocyte-specific Mll4 knockout mice showed mild inhibition of steatosis. Pro-inflammatory M1 polarization is decreased and anti-inflammatory M2 polarization is increased in liver macrophages from myeloid-specific Mll4 knockout mice. Importantly, we show that histone H3-lysine 4 methylation mediated by the MLL4-complex plays a critical role in promoting the expression of Ccl2 in hepatocytes and M1 marker genes in macrophages. Our results demonstrate that MLL4, through the NF-κB-MLL4 regulatory axis, exacerbates steatohepatitis in the context of an inflammatory response and represents a potential therapeutic target for NASH.

Mulberry galacto-oligosaccharides ameliorates non-alcoholic fatty liver disease in mice induced by a high-fat diet

A type of oligosaccharide named mulberry galacto-oligosaccharides (MGO), was isolated from mulberry with a galactose-only, weighs 987 Da and displays diverse biological properties. The objective of this work was to investigate the protective effects of MGO in non-alcoholic fatty liver disease (NAFLD) mice. The results showed that MGO can reduce the body weight and liver weight of NAFLD mice, and reduce the levels of NEFA, TG, TC and LDL-C in serum and liver as well as the activities of AST and ALT. Increase HDL-C content, SOD, and GSH activity in serum and improve pathological damage. MGO regulates the AMPK lipid metabolism pathway, upregulates the expression of ATGL, downregulates the expression of SREBP-1, inhibits lipogenesis, and promotes lipolysis. MGO alleviates liver function damage in NAFLD mice, improves blood lipids, liver metabolism, and increases the body’s antioxidant capacity, suggesting MGO potential as a dietary supplement and functional food to combat HFD-induced NAFLD.

Protective Effect of Modified Suanmei-Tang on Metabolic-Associated Fatty Liver Disease: An Integrated Strategy of Network Pharmacology, Metabolomics, and Transcriptomics

Protective Effect of Modified Suanmei-Tang on Metabolic-Associated Fatty Liver Disease: An Integrated Strategy of Network Pharmacology, Metabolomics, and Transcriptomics

Female C57BL/6 Mice Exhibit Protection Against Nonalcoholic Fatty Liver Disease and Diabesity Accompanied by Differential Regulation of Hepatic Lipocalin Prostaglandin D2 Synthase

Female C57BL/6 Mice Exhibit Protection Against Nonalcoholic Fatty Liver Disease and Diabesity Accompanied by Differential Regulation of Hepatic Lipocalin Prostaglandin D2 Synthase