To examine the relationship between lipid profile and non-alcoholic fatty liver (NAFL), compare the predictive strengths of different lipid indicators to NAFL, and explore the possible mechanisms.

Male workers from a baseline survey of a cohort of workers in southern China were included. Basic information was collected through face-to-face interviews. Plasma concentrations of fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were determined using a blood biochemical analyzer. Liver sonography was used to identify NAFL cases. Regression models were used to calculate ORs, and examine the association between C-reactive protein (CRP) levels and lipid profiles. Restricted cubic spline regression with four knots was used to examine the dose-response relationship, and mediation analysis was employed to examine the mediation effect.

h Among the 4016 male workers, 829 (20.64%) were diagnosed with NAFL. Compared with normal lipid profile, individuals with abnormal lipid profile had higher prevalence of NAFL (OR=2.27, 95%CI: 1.85-2.79 for TG; OR=1.45, 95%CI: 1.03-2.04 for TC; OR=1.56, 95%CI: 1.21-2.02 for HDL; OR=1.65, 95%CI: 1.25-2.18 for LDL; OR=2.28, 95%CI: 1.87-2.77 for dyslipidaemia) after adjusting for potential confounders. Dose-response relationships were observed among TG, HDL, and NAFL. In addition, no significant mediation effect of C-reactive protein (CRP) was found in the association between lipid profiles and NAFL.

Abnormal TG, TC, HDL, and LDL levels were all positively associated with NAFL, while CRP has no mediating effect, and TG tended to be a better predictor of NAFL.

Adipogenesis is the healthy expansion of white adipose tissue (WAT), serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body. Therefore, the identification of novel regulatory molecules in adipogenesis, specifically membrane receptors such as G protein-coupled receptors (GPCRs), holds significant clinical promise. These receptors can serve as viable targets for pharmaceuticals, offering potential for restoring metabolic homeostasis in individuals with obesity. We utilized trajectory inference methods to analyze three distinct single-nucleus sequencing (sNuc-seq) datasets of adipose tissue and systematically identified GPCRs with the potential to regulate adipogenesis. Through verification in primary adipose progenitor cells (APCs) of mice, we discovered that ADGRD1 promoted the differentiation of APCs, while GPR39 inhibits this process. In the obese mouse model induced by a high-fat diet (HFD), both gain-of-function and loss-of-function studies validated that ADGRD1 promoted adipogenesis, thereby improving metabolic homeostasis, while GPR39 inhibited adipogenesis, leading to metabolic dysfunction. Additionally, through the analysis of 2,400 ChIP-seq data and 1,204 bulk RNA-seq data, we found that the transcription factors (TFs) MEF2D and TCF12 regulated the expression of ADGRD1 and GPR39, respectively. Our study revealed the regulatory role of GPCRs in adipogenesis, providing novel targets for clinical intervention of metabolic dysfunction in obese patients.

Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease.

This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases.

We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.

Liver steatosis (LS) is a condition that is characterised by hepatic fat accumulation unrelated to significant alcohol consumption. This study explored the serum proteomic profile associated with LS in people living with HIV (PLWH).

The study cohort comprised 266 PLWH, 21.1% and 78.9% of whom had LS and no LS, respectively. Serum samples were analysed using liquid chromatography coupled with mass spectrometry (LC-MS).

Among the 220 proteins detected, afamin (AFM) and apolipoprotein F (APOF) were identified as proteins associated with LS. Differential expression of AFM and APOF was observed in under- and normoweight patients, emphasising their potential as biomarkers in patients without overweight or obesity.

These findings suggest that the identified proteins could serve as promising biomarkers of LS in PLWH, paving the way for further investigations into the roles of these proteins in LS development in this unique population.

Not required for Editorials.

The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in regulating lipid metabolism in vitro, its specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in MASH pathogenesis and explored the underlying mechanisms.

MASH models were established using mice fed either a methionine- and choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific SOX9 deletion or overexpression was performed. Lipidomic analyses were conducted to assess how SOX9 influences hepatic lipid metabolism. RNA sequencing was employed to identify pathways modulated by SOX9 during MASH progression. To elucidate the mechanism further, HepG2 cells were treated with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.

SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific SOX9 deletion exacerbated MCD-induced MASH, whereas overexpression of SOX9 mitigated high-fat, high-fructose-induced MASH. Lipidomic and RNA sequencing analyses revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, SOX9 deletion inhibited AMPK pathway activation, while SOX9 overexpression enhanced it. Notably, administration of an AMPK inhibitor negated the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.

Our findings demonstrate that SOX9 overexpression alleviates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target for treating MASH.

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a growing health concern worldwide. Among the pursuit of therapeutic interventions, interest in natural bioactive compounds has intensified because of their potential hepatoprotective effects. This systematic review aims to evaluate the impact of plant-derived hydrolysates and peptides on MAFLD through the current literatures, encompassing their mechanisms of action. Key outcomes evaluated included changes in liver enzymes, liver lipid content, inflammation markers, and histopathological improvements. Preliminary findings suggest a potential beneficial effect of plant-derived hydrolysates and peptides on the improvement of MAFLD-related parameters, with mechanisms implicating antioxidant, anti-inflammatory, and lipid-lowering properties. This review highlights emerging evidence supporting the potential therapeutic role of plant-derived hydrolysates and peptides in the management of MAFLD. However, more well-designed clinical trials with larger sample sizes and longer durations are warranted to elucidate their efficacy, optimal dose, and long-term safety.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves hepatic lipid accumulation, inflammation, and fibrosis. It can progress to cirrhosis or hepatocellular carcinoma without timely treatment. Current treatment options for MASH are limited. This study explores the therapeutic effects of fluorofenidone (AKF-PD), a novel small-molecule compound with antifibrotic and anti-inflammatory properties, on MASH in mouse model. Mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) were treated with AKF-PD, resulting in reduced serum ALT, AST, hepatic lipid accumulation, liver inflammation, and fibrosis. Network pharmacology and RNA-sequencing analyses suggested that AKF-PD influenced multiple metabolic, inflammatory, and fibrosis-related pathways. Further experiments verified that AKF-PD activated hepatic AMPK signaling, leading to the inhibition of the downstream SREBF1/SCD1 pathway and the activation of autophagy. Additionally, AKF-PD suppressed the expression of various inflammatory factors, reduced macrophage infiltration, and inhibited NLRP3 inflammasome activation. Moreover, AKF-PD attenuated liver fibrosis by inhibiting TGFβ1/SMAD signaling. In conclusion, this study reveals that AKF-PD effectively decreases hepatic lipid accumulation, liver inflammation and fibrosis in a CDAHFD-induced MASH model, positioning AKF-PD as a promising candidate for the treatment of MASH.

Steatosis is characterized by an increase in free fatty acids, such as palmitic acid (PA), in hepatocytes and the accumulation of triglycerides in the liver. However, the role of intracellular autophagy in PA accumulation-induced hepatotoxicity is not clearly understood. Therefore, in this study, we investigated the effects of PA on autophagy in hepatocytes and its underlying mechanism of action. Treatment of HepG2 cells with PA induced a significant increase in intracellular p62 and LC3-II levels, suggesting inhibition of autophagy. Furthermore, PA inhibited autophagic flux in HepG2 cells, as monitored using GFP-RFP-LC3. Mechanistically, PA increased the phosphorylation of the Ser12 and Thr29 residues of LC3, which are autophagy inhibition markers, through protein kinase A (PKA) and protein kinase C (PKC) signaling. Finally, PKA and PKC inhibitors restored PA-induced autophagic flux inhibition, reduced intracellular lipid accumulation, and rescued the altered expression of lipogenic genes, such as SREBP-1c, in HepG2 cells. Thus, our study demonstrates the mechanism of autophagy inhibition by PA in hepatocytes and provides a potential therapeutic approach for preventing and treating hepatic steatosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, represents a prevalent condition ranging from simple steatosis to advanced stages associated with liver cancer. Asymptomatic presentation in the majority of cases underscores the need for non-invasive, cost-effective methods to stratify degree of hepatic steatosis. This cross-sectional study aimed to assess the association between obesity and lipid-related indices with the degree of hepatic steatosis in MASLD patients. 150 individuals recently diagnosed with metabolic dysfunction-associated steatotic liver disease were recruited. Anthropometric measurements, including weight, height, and waist circumference (WC), were taken, alongside biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides (TG), high-density lipoprotein, low-density lipoprotein, and fasting plasma glucose, following a 12-h fasting period. Various indicators of obesity and lipid metabolism, including body mass index, waist-to-height ratio (WHtR), a body shape index, lipid accumulation product (LAP), triglyceride-glucose index (TyG), visceral adiposity index, and hepatic steatosis index (HSI), were calculated. The diagnosis of MASLD and degree of hepatic steatosis were established through abdominal ultrasound examination. Data analysis was performed utilizing SPSS version 22. All the investigated indices displayed an area under the curve (AUC) surpassing 0.5, implying a correlation with the degree of hepatic steatosis. Notably, TyG-WC, TyG-WHtR, LAP, and a cardiometabolic obesity index showed the highest AUC values (> 0.7), indicating a relatively strong association with degree of hepatic steatosis. Specifically, in females, TyG-WC (AUC = 0.797, 95% CI 0.712-0.882, threshold = 865.991), while in males, LAP (AUC = 0.746, 95% CI 0.593-0.899, threshold = 74.290), demonstrated the highest AUC values. TyG-WHtR, TyG-WC, and LAP exhibited significant correlations with the degree of hepatic steatosis. Given their non-invasive nature and easy measurement, they hold promise for potential clinical utility, pending validation in additional studies.

Obesity is detrimental to liver health. Weight-adjusted waist circumference (WWI) is a new indicator of obesity that is superior to body mass index (BMI) and waist circumference (WC) in predicting obesity. There are limited studies on the relationship between Metabolic Associated Fatty Liver Disease (MASLD) and WWI. Therefore, this study aimed to investigate the association between WWI, Controlled Attenuation Parameters (CAP), and Liver Stiffness Measurement (LSM), with special attention to gender differences.

This cross-sectional study included participants from the 2017 to 2020 National Health and Nutrition Examination Survey (NHANES). The study used multiple linear regression models, smoothed curves, and threshold effects analyses to describe the relationships between variables. Multiple regression analyses were used to examine the associations between the four obesity indicators and CAP and LSM. Subject work characteristics (ROC) curves were used to assess the predictive value of WWI and other traditional obesity indicators for hepatic steatosis and liver fibrosis, and predictive power was assessed by area under the curve (AUC).

The study involved 6713 participants, including 3072 men (46%) and 3641 women (54%). The results showed that among female participants, higher WWI was associated with hepatic steatosis (OR = 1.71, 95% CI: 1.43, 2.04; P < 0.0001) and hepatic fibrosis (OR = 2.11, 95% CI: 1.58, 2.84; P < 0.0001). Smoothed curve fitting of WWI versus CAP showed a statistically significant positive correlation between WWI in male and female participants There was a statistically significant positive correlation with CAP for both male and female participants. The same significant non-linear relationship was found between WWI and LSM, with no significant difference between males and females. WWI was also a good predictor of hepatic steatosis compared to other obesity indicators and was more pronounced in male participants (AUC = 0.8224). Whereas in the comparison of WWI with LSM, wBMI was a better predictor in female participants (AUC = 0.7751).

Based on this study, WWI was significantly associated with the risk of hepatic steatosis and hepatic fibrosis in women, suggesting the potential of WWI as a screening tool. Due to the cross-sectional design, causality cannot be inferred. Longitudinal studies are needed to validate our findings.

The management of hypertensive disease in pregnancy is currently guided by practice recommendations based largely on observational data from a half century ago and has changed only superficially since that time. These recommendations are both narrowly prescriptive (women without traditional features of severe disease should all be delivered at exactly 370/7 weeks) and at the same time frustratingly ambiguous (the presence of epigastric pain unresponsive to repeat analgesics precludes expectant management at any gestational age, regardless of laboratory studies). Guidelines that ignore recent data from the obstetric, pediatric, and internal medicine literature too often lead practitioners to be more aggressive than necessary in the delivery of very premature pregnancies, and, conversely, more complacent than patient safety would support in prolonging pregnancy with advanced fetal maturity. We present here an alternative, organ-specific-based approach to the management of gestational hypertension that allows and encourages practitioners to formulate a management plan based on a thoughtful and, when possible, evidence-based synthesis of the continuous variables of blood pressure, degree of organ dysfunction and response to treatment, gestational age, and patient balancing of maternal and fetal/neonatal risks. Such clinical care is more complex and nuanced than simply basing life-altering critical management decisions, including timing of delivery, on whether the patient does, or does not have any one of the conditions described by box 4 of the current American College of Obstetricians and Gynecologists practice guidelines. Nonetheless, we believe this approach will not only improve care but will also open the door to useful investigations into prevention and management of the various entities traditionally considered as the same disease process. KEY POINTS: · Traditional approaches to preeclampsia are not evidence based.. · The use of such approaches has resulted in stagnant maternal morbidity and mortality ratios.. · The consideration of disease severity as binary is particularly counterproductive.. · An organ-based approach will facilitate evidence-based individualization of care..

Valsartan (VAL) is commonly prescribed for patients with cardiovascular disease (CVD) to lower blood pressure, reduce heart failure risk, and prevent heart attacks or strokes by blocking the effects of angiotensin II. Many patients with CVD also suffer from metabolic dysfunction-associated steatohepatitis (MASH), which disrupts several xenobiotic transporters, affecting the pharmacokinetics of numerous drugs. Medications used in patients to treat comorbidities associated with MASH may be subject to this altered disposition and potential toxicity. This study aimed to assess how MASH alters the pharmacokinetics of VAL using a rodent model that mimics human MASH. MASH was induced in rats via a methionine- and choline-deficient (MCD) diet. Rats received VAL-a substrate of organic anion-transporting polypeptide (OATP) 1B1/1B3 and reported for multidrug resistance-associated protein-2-(2 mg/kg) through intravenous injection to isolate hepatic transport processes, and bile, serum, and liver concentrations measured using liquid chromatography-tandem mass spectrometry. Consistent with MASH progression, MCD rats presented with more gross pathology, including increased liver-to-body weight ratios, along with macrosteatosis, hepatocyte ballooning, and lobular inflammation. In MCD rats, the expression of Oatp1b2 was significantly reduced, and Mrp2 was internalized, resulting in higher systemic exposure to VAL compared with controls. Additionally, cumulative biliary excretion of VAL was lower in MCD rats. To further assess VAL disposition in MASH, transport kinetics were evaluated in human embryonic kidney 293 cells overexpressing OATP1B1 or OATP1B3, revealing similar affinity for VAL between both transporters. These findings suggest that changes in OATP function in MASH may alter VAL pharmacokinetics, which may have implications for personalized treatments. SIGNIFICANCE STATEMENT: Although expression of drug transporters in metabolic dysfunction-associated steatohepatitis (MASH) has been explored, the combined effect between MASH and genetic loss of transporters on the disposition of sartan drugs has not been determined. This study applied liquid chromatography-tandem mass spectrometry analyses and immunohistological staining to assess drug disposition and identify alterations to drug transporters in rodents on a methionine- and choline-deficient diet. The observations made in this study have significant implications regarding its disposition in the context of hepatic dysfunction associated with MASH.

Sarcopenic obesity (SO), characterized by the coexistence of obesity and sarcopenia, is an increasingly prevalent condition in aging populations, associated with numerous adverse health outcomes. We aimed to identify and validate an explainable prediction model of SO using easily available clinical characteristics.

A preliminary cohort of 1,431 participants from three community regions in Ziyang city, China, was used for model development and internal validation. For external validation, we utilized data from 832 residents of multi-center nursing homes.

The diagnosis of SO was based on the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) criteria. Five machine learning models (support vector machine, logistic regression, random forest, light gradient boosting machine, and extreme gradient boosting) were used to predict SO. The performance of these models was assessed by the area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) approach was used for model interpretation.

After feature reduction, an 8-feature model demonstrated good predictive ability. Among the five models tested, the support vector machine (SVM) model performed best in SO prediction in both internal (AUC = 0.862) and external (AUC = 0.785) validation sets. The eight key predictors identified were BMI, gender, neck circumference, waist circumference, thigh circumference, time to full tandem standing, time to five-times sit-to-stand, and age. SHAP analysis revealed BMI and gender as the most influential predictors. To facilitate the utilization of the SVM model in clinical setting, we developed a web application ( https://svcpredictapp.streamlit.app/ ).

We developed an explainable machine learning model to predict SO in aging community and nursing populations. This model offers a novel, accessible, and interpretable approach to SO prediction with potential to enhance early detection and intervention strategies. Further studies are warranted to validate our model in diverse populations and evaluate its impact on patient outcomes when integrated into comprehensive geriatric assessments.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, primarily driven by the escalating obesity epidemic worldwide. MASLD, a spectrum of liver disorders, can progress to more severe conditions, metabolic dysfunction-associated steatohepatitis (MASH), ultimately culminating in hepatocellular carcinoma (HCC). Given the complex nature of MASLD, there is an urgent need to develop robust risk prediction models and design specialized cancer screening initiatives tailored specifically for individuals with MASLD. This study aimed to identify genes exhibiting trending expression patterns that could serve as potential biomarkers or therapeutic targets. Our approach involved analyzing expression patterns across the five stages of MASLD development and progression. Notably, we introduced an innovative two-phase classification-MASLD occurrence and MASLD progression-instead of categorizing differentially expressed genes (DEGs) into multiple types. Leveraging LASSO regression models, we demonstrated their relatively strong capability to predict and distinguish both MASLD occurrence and progression. Furthermore, our analysis identified CYP7A1 and TNFRSF12A as significantly associated with the prognosis of MASLD progressing to HCC. These findings contribute to the understanding of gene expression dynamics in MASLD and may pave the way for the development of effective prognostic tools and targeted therapies in the realm of liver disease.

Nonalcoholic fatty liver disease (NAFLD) is mainly related to genetics, obesity, insulin resistance, and type 2 diabetes. Probiotic Lactiplantibacillus plantarum Lb41 (Lb41) has not been reported to have hepatoprotective effects. Therefore, the aim of this study is to investigate the preventive effects of Lb41 against NAFLD in high-fat diet (HFD)-fed mice for preventing NAFLD.

To induce fatty liver, the mice were given HFD for 5 weeks, followed by silymarin (200 mg/kg) or Lb41 (108 or 109 colony forming units/day) with the HFD for 7 weeks. After 12 weeks, body weight, histological change, serum and hepatic lipid profiles, etc. was performed compared to control and silymarin.

Lb41 had significantly reduced body weight (4.87 g) and serum lipids (triglycerides (77.64%), total cholesterol (67.53%), and low-density lipoprotein (40.50%) compared with the HFD group (P < 0.05). Lb41 significantly relieved HFD-associated hepatic injury by reducing aspartate transaminase (0.49-0.57 fold), alanine transaminase (0.49-0.51 fold), and alkaline phosphatase (0.76-0.90 fold) (P < 0.05). Additionally, they had decreased expression levels of peroxisome proliferator-activated receptor (PPAR) γ and sterol regulatory element-binding protein 1c and increased the expression levels of acyl-CoA oxidase, PPARα, carnitine palmitoyltransferase 1, acetyl CoA carboxylase 1, and fatty acid synthase in liver cells. Insulin and leptin levels decreased in the Lb41 treatment group compared with those in the HFD group. Meanwhile, adiponectin levels increased, similar to those in the normal diet group.

Based on these findings, Lb41 probiotics have possible hepatoprotective effects and could be used as functional food materials.

UbiA prenyltransferase domain containing 1 (Ubiad1) has the potential to affect cholesterol and phospholipid levels in different cell types. We previously identified Ubiad1 as a candidate gene for regulating subcutaneous fat pad weight in a mouse genome-wide association study. Here we evaluated the relationship between Ubiad1 and obesity-related traits in cohorts of humans and mice, and in Ubiad1+/- mice fed a high-fat diet. In both humans and mice, adipose tissue Ubiad1 mRNA expression correlated negatively with adiposity and positively with mitochondria-related genes. To determine the role of Ubiad1 in high-fat diet-induced obesity, we disrupted the Ubiad1 gene in mice. Deletion of Ubiad1 was embryonically lethal in C57BL/6 N mice, preventing analysis of adult Ubiad1-/- mice. Thus, male and female Ubiad1+/+ and Ubiad1+/- mice were fed high-fat diet for 10 weeks, with no difference in weight gain and adipose tissue organ weights observed between the genotypes. Analysis of liver mRNA expression revealed that Ubiad1 heterozygosis (Ubiad1+/-) altered several pathways involved in lipid metabolism. Detailed lipid quantification with HPLC-qTOF/MS showed increased levels of hepatic ceramides in female Ubiad1+/- mice, whereas phosphatidylglycerols, phosohatidylinositol and lysophosphatidylethanolamines were reduced in male Ubiad1+/- mice. Our findings reveal sex-specific effects of Ubiad1 expression on hepatic lipid metabolism.

Cardiovascular disease morbidity and mortality rates are high in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). The objective of this study was to analyze the risk factors and differences between lean MAFLD and overweight MAFLD, and establish and validate a nomogram model for predicting lean MAFLD.

This retrospective cross-sectional study included 4363 participants who underwent annual health checkup at Yuyao from 2019 to 2022. The study population was stratified into three groups: non-MAFLD, lean MAFLD (defined as the presence of fatty liver changes as determined by ultrasound in individuals with a BMI < 25 kg/m2), and overweight MAFLD (BMI ≥ 25.0 kg/m2). Subsequent modeling analysis was conducted in a population that included healthy subjects with < 25 kg/m2 (n = 2104) and subjects with lean MAFLD (n = 849). The study population was randomly split (7:3 ratio) to a training vs. a validation cohort. Risk factors for lean MAFLD was identify by multivariate regression of the training cohort, and used to construct a nomogram to estimate the probability of lean MAFLD. Model performance was examined using the receiver operating characteristic (ROC) curve analysis and k-fold cross-validation (k = 5). Decision curve analysis (DCA) was applied to evaluate the clinical usefulness of the prediction model.

The multivariate regression analysis indicated that the triglycerides and glucose index (TyG) was the most significant risk factor for lean MAFLD (OR: 4.03, 95% CI 2.806-5.786). The restricted cubic spline curves (RCS) regression model demonstrated that the relationships between systolic pressure (SBP), alanine aminotransferase (ALT), serum urate (UA), total cholesterol (TCHO), triglyceride (TG), triglyceride glucose (TyG) index, high density lipoprotein cholesterol (HDLC), and MAFLD were nonlinear and the cutoff values for lean MAFLD and overweight MAFLD were different. The nomogram was constructed based on seven predictors: glycosylated hemoglobin A1c (HbA1c), serum ferritin (SF), ALT, UA, BMI, TyG index, and age. In the validation cohort, the area under the ROC curve was 0.866 (95% CI 0.842-0.891), with 83.8% sensitivity and 76.6% specificity at the optimal cutoff. The PPV and NPV was 63.3% and 90.8%, respectively. Furthermore, we used fivefold cross-validation and the average area under the ROC curve was 0.866 (Figure S3). The calibration curves for the model's predictions and the actual outcomes were in good agreement. The DCA findings demonstrated that the nomogram model was clinically useful throughout a broad threshold probability range.

Lean and overweight MAFLD exhibit distinct metabolic profiles. The nomogram model developed in this study is designed to assist clinicians in the early identification of high-risk individuals with lean MAFLD, including those with a normal BMI but at metabolic risk, as well as those with abnormal blood lipid, glucose, uric acid or transaminase levels. In addition, this model enhances screening efforts in communities and medical screening centers, ultimately ensuring more timely and effective medical services for patients.

Complications of diabetes mellitus have significant impacts on morbidity, mortality, quality of life, and health costs for individuals. Setting and achieving glycemic targets to prevent these complications is a top priority when managing diabetes. However, patients often already have complications when diagnosed with diabetes mellitus. Therefore, methods to prevent disease progression become a crucial component of diabetes management. The purpose of this article is to review glycemic targets and methods of screening and managing diabetes-related complications.

A PubMed review of the literature pertaining to diabetes mellitus, glycemic targets, microvascular complications, and macrovascular complications was conducted. We reviewed articles published between 1993 and 2024. Guidelines published by nationally recognized organizations in the fields of diabetes, nephrology, and cardiology were referenced. Public health statistics obtained by the Center for Disease Control and Prevention and the National Kidney Foundation were used.

Achieving glycemic targets and screening for diabetes-related complications at appropriate intervals remains the key factor for early detection and intervention. An algorithmic approach to glycemic management based on individual risk factors is beneficial in choosing pharmacotherapy.

The consequences of diabetes-related complications can be detrimental. However, achieving and maintaining glycemic targets combined with diligent screening, reduction of risk factors, and prompt treatment can halt disease progression.

This study aimed to evaluate the prevalence and risk factors of non-alcoholic fatty liver disease (NAFLD) among Dayak communities in Malaysia, shedding light on an underexplored population.

A cross-sectional study was undertaken among Dayak villagers in Sarawak aged 18 years and above using an interview-based questionnaire, followed by an anthropometric measurement, a blood test and an abdominal ultrasound.

A total of 324 participants met the inclusion criteria. Among them, 42.9% were men, and the mean age was 49.85±14.9 years. The prevalence of NAFLD was substantially high at 58%, with 43.1% of the participants having mild fatty liver (grade 1). NAFLD was closely associated with waist circumference and body mass index (BMI) (P<0.001). Central obesity, as indicated by waist circumference and BMI, emerged as a potent risk factor, with higher values correlating with an increased likelihood of NAFLD. A higher prevalence of NAFLD was observed in the participants with an advancing age, an elevated triglyceride level (66.7%) and a lower high-density lipoprotein cholesterol level (81.6%). However, these associations did not remain significant in the multivariate analysis. Gallstones, which share common risk factors with NAFLD, were not significantly associated with NAFLD in this population (P=0.853).

This study defines the prevalence and association of NAFLD with sociodemographic characteristics, health profiles and gallstone disease among indigenous villages in Dayak communities. A high BMI and central obesity are found to be independent risk factors of NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is understudied among US adolescents despite rising obesity rates.

This study analysed the prevalence and trends of obesity and MASLD among US adolescents aged 12-17 using data from the National Health and Nutrition Examination Survey (NHANES). We developed a new screening model utilizing FibroScan-measured controlled attenuation parameter (CAP) scores, body measurements and blood chemistry data from 2017 to 2020 to assist in analysing MASLD trends from 1999 to 2020.

Between 2017 and 2020, the prevalence of obesity and MASLD was approximately 20%, with about 70% of obese adolescents affected by MASLD. The condition was more common in boys, particularly among Mexican American adolescents. Additionally, 97.2% of those with NAFLD also had MASLD. Adolescents with MASLD had significantly higher body weight, waist circumference, triglyceride levels and alanine transaminase (ALT) levels, along with lower high-density lipoprotein (HDL) cholesterol and an increased risk of liver fibrosis. Insufficient physical activity and poor diet quality were key risk factors for developing MASLD. From 1999 to 2020, the prevalence of MASLD rose significantly, paralleling the increasing rates of obesity.

The study underscores the pressing need to screen at-risk adolescents for metabolic issues associated with steatotic liver diseases, given the rising obesity rates among adolescents. The high overlap between MASLD and NAFLD diagnoses indicates that the transition from NAFLD to MASLD can be effectively integrated into paediatric practice.

Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development.

Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism.

The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.

The current research was to investigate the relationship between prognostic nutritional index (PNI) and mortality, with a focus on all-cause and cardiovascular disease (CVD) mortality, for those with non-alcoholic fatty liver disease (NAFLD).

Data from 20,142 patients who participated in the National Health and Nutrition Examination Survey (NHANES), which was carried out between 2005 and 2014, were included in this research. To examine the relationship between PNI and both all-cause and cardiovascular mortality, we employed weighted Cox regression models with multiple variables. Kaplan-Meier survival curves were utilized to visualize the survival distribution across different levels of PNI. The non-linear association between PNI and mortality was addressed through penalized spline smoothing. Subgroup analyses were conducted to examine the potential influence of relevant clinical variables on the relationship between PNI and mortality. The precision of PNI in forecasting the outcome of survival was assessed as well using time-dependent receiver operating characteristic curve (ROC) analysis.

Kaplan-Meier analysis linked higher PNI to significantly reduced all-cause and CVD mortality. Multivariable Cox models demonstrated that increasing PNI consistently lowered mortality risks. With a threshold value of 50.5, the link between PNI and mortality showed a non-linear pattern after adjusting for confounding factors. Subgroup analyses confirmed robust associations, particularly in race, education, BMI, and fibrosis. Time-dependent ROC analysis highlighted the strong predictive performance of PNI across various time points.

PNI played a significant role as an effective predictor of prognosis in individuals diagnosed with NAFLD.

Artemisia capillaris Thunb. (ACT) is a plant in the Asteraceae family. Its traditional effects are to clear away dampness and heat, promote gallbladder and reduce jaundice. Traditional Chinese medicine believes that MASLD is a damp-heat syndrome. The group's previous study showed that Artemisia capillaris Thunb. Water Extract (ACTE) has an improved effect on MASLD.

In order to further understand its mechanism of action, this study established a mouse MASLD model and a HepG2 cell lipid droplet model, combined small RNA sequencing and miRNA transfection experiments, to explore the mechanism of ACTE to improve MASLD by modulating miRNA-targeted mRNA. Non-targeted metabolomics method was used to detect and analyze ACTE.

This study screened miR-34a-5p and confirmed its target mRNA-Sirtuin 1 (Sirt1). MASLD induced high expression of miR-34a-5p and low expression of Sirt1, and ACE reversed these changes. When overexpressing miR-34a-5p or knocking down Sirt1, the effect of ACE in reducing PO (palmitic acid and oleic acid complex)-induced lipid accumulation in HepG2 cells was attenuated. ACTE reduces the expression of FASN, SCD1, ACC, and SREBP-1c, promotes the expression of CPT-1 and HSL, thereby reducing lipid accumulation.

ACTE activates Sirt1 by inhibiting the expression of miR-34a-5p, thereby reducing liver lipid accumulation and improving HFD-induced MASLD. These findings highlight the potential of ACTE in reducing weight, controlling obesity, and improving lipid metabolism disorders.

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.

This study aimed to determine whether remnant cholesterol (RC) and its variability can predict the onset of metabolic dysfunction-associated steatotic liver disease (MASLD) independently of low-density lipoprotein cholesterol (LDL-C) levels. A longitudinal cohort study involving 43,065 participants who underwent at least two physical examinations was conducted. This study used Cox proportional hazards models to assess the relationships among RC quartile levels (Q1-Q4), visit-to-visit variability, and the risk of MASLD. This variability was quantified using several metrics: standard deviation (SD), logSD, average real variability (ARV), logARV, mean absolute deviation (MAD), and logMAD. Concurrently, this study utilized a combined analysis of RC and LDL-C groups to assess the independent risk of MASLD associated with RC. During a mean visit-to-visit of 3.19 years (SD 2.06 years), 8374 patients (19.45%) developed MASLD. Compared with Q1, Q4 was associated with a significantly greater risk of MASLD (hazard ratio [HR] 1.309, 95% confidence interval [CI] 1.220-1.403, P < 0.001). The fully adjusted Cox model revealed that the HRs of SD, logSD, ARV, logARV, MAD and logMAD were 1.400 (95% CI 1.305-1.502), 1.278 (95% CI 1.188-1.374), 1.152 (95% CI 1.079-1.229), 1.183 (95% CI 1.140-1.227), 1.578 (95% CI 1.433-1.737) and 1.263 (95% CI 1.175-1.358), respectively. In both LDL-C subgroups (≥ 3.4 mmol/L and < 3.4 mmol/L), high baseline RC was associated with elevated MASLD risk (HR 1.208, 95% CI 1.148-1.270, P < 0.001; HR 1.246, 95% CI 1.129-1.374, P < 0.001). RC levels were independently associated with MASLD in healthy individuals, irrespective of LDL-C level. The variability of RC during visit-to-visit periods provides a predictive marker for identifying individuals at heightened risk of MASLD.

Morchella esculenta is a valuable edible fungus with multidimensional bioactivities; however, research on M. esculenta protein and its beneficial effects on nonalcoholic fatty liver disease (NAFLD) have been limited. In this study, M. esculenta protein (MEP) with 80.59% protein content was prepared, isolated, and characterized by the complete amino acid composition. The main molecular weight of the protein ranged from 65 to 120 kDa, with 100 kDa being the most dominant band, and it exhibited an alpha helix structure when analyzed by FT-IR and circular dichroism analysis. MEP could regulate body weight, fat accumulation, and alleviate lipid metabolism in adipose tissues in mice with high-fat diet-induced NAFLD. MEP prevented hepatic lipotoxicity, which was reflected in attenuating liver steatosis in vitro and in vivo, thereby regulating the levels of related factors involved in lipid metabolism (e.g., PPARs, HNF-4, SREBP, FASN, ACC-1, and CD36). Furthermore, it inhibited oxidative stress response, which can be attributed to the activation of the MAPK/PGC-1α pathway. Additionally, MEP exhibited probiotic effects, as demonstrated by the altered gut microbiota composition and improved the intestinal barrier integrity. Thus, this study confirmed the preventive effect of MEP against NAFLD by regulating the gut-liver cross-talk, which provided a theoretical basis for the development and utilization of M. esculenta.

The weight-adjusted waist index (WWI) is a novel indicator of obesity, and its association with mortality in stroke patients remains unknown. We aimed to explore these associations through a national longitudinal cohort study.

We included stroke survivors from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 who were followed up until December 31, 2019. The study outcomes were all-cause and cardiovascular disease (CVD) mortality in stroke patients. A total of 1427 stroke patients were enrolled, and after a median follow-up duration of 83 months, 624 stroke patients died, including 251 from CVD. Kaplan‒Meier survival analyses indicated that WWI was significantly associated with the probability of survival over time in stroke patients (log-rank tests, both p < 0.0001). After adjusting for confounders, WWI was significantly and positively associated with all-cause and CVD mortality after stroke. Restricted cubic spline analysis revealed that WWI was linearly associated with all-cause mortality and nonlinearly associated with CVD mortality. Stratified analyses suggested that sex significantly influenced the effect of WWI on all-cause mortality in stroke patients. Additional body mass index (BMI) adjustments did not significantly change the results.

WWI was positively associated with all-cause and CVD mortality in stroke patients, independent of BMI. These effects were present only in men. These findings suggest that WWI is an independent prognostic factor in stroke patients and that maintaining appropriate WWI values can help improve the prognosis of stroke survivors.

There is limited understanding of socioeconomic inequality in multimorbidity in Iran. This study aims to investigate socioeconomic inequality in multimorbidity among adults in western Iran. Data from the Ravansar Non-Communicable Disease (RaNCD) cohort study were used in this cross-sectional study. A sample of 10,047 adults aged 35-65 years was analyzed. Principal component analysis was utilized to determine socioeconomic status (SES). The normalized concentration index (NCI) was used to assess the extent of socioeconomic disparities in multimorbidity. Decomposition analysis was conducted to identify and calculate the factors contributing to multimorbidity inequality. In this study, the prevalence of having at least two NCDs was 9.07%, while the prevalence of having at least three NCDs was 2.87%, and four or more NCDs was 1.25%. The NCI for multimorbidity was -0.061 (P < 0.001), indicating a higher concentration of multimorbidity among individuals with low SES. Age (52.5%), body mass index (BMI) (29.4%), gender (27.5%), physical activity (25.1%), and SES (15%) were identified as significant factors contributing to the increased inequality in multimorbidity. The study findings identified age, gender, BMI, physical activity, and SES as key factors driving multimorbidity disparities. It is recommended that health policymakers prioritize health interventions aimed at reducing socioeconomic inequalities in multimorbidity, particularly for low-SES groups, women, obese individuals, and older adults.

Attenuated insulin-sensitivity (IS) is a characteristic of type 2 diabetes (T2D) and is closely linked to non-alcoholic fatty liver disease (NAFLD). In recent years, many surrogate markers of IS have emerged to predict NAFLD. A natural log transformation of the glucose disposal rate (loge GDR) has been proposed as a new model for IS in patients with T2D. Our aim is to explore the correlation between loge GDR and NAFLD in normoalbuminuric patients with T2D.

A total of 1227 normoalbuminuric patients with T2D were involved in our study. NAFLD was evaluated by ultrasound. Biochemical and clinical data were collected, including parameters essential for calculating the loge GDR (triglycerides, urinary albumin-to-creatinine ratio, γ-glutamyl transferase and body mass index), as well as other relevant covariates required for adjustment. The relationship between the loge GDR and NAFLD was analyzed.

NAFLD patients showed lower loge GDR values than non-NAFLD (P < 0.001). As the loge GDR tertiles increased, the prevalence of NAFLD was decreased (P < 0.001). Multivariate analysis displayed that loge GDR was independently corrected with NAFLD (OR: 0.084; 95% CI: 0.040-0.177). Furthermore, receiver operating characteristic (ROC) analysis showed that loge GDR (area under the curves: 0.797) was superior to other evaluation variables.

The loge GDR was strongly associated with NAFLD and might be a useful predictor in normoalbuminuric patients with T2D.

Obesity and type 2 diabetes (T2DM) are major risk factors for hepatic steatosis. Diet or bariatric surgery can reduce liver volume, fat content, and inflammation. However, little is known about their effects on liver function, as evaluated here using the LiMAx test.

In the MetaSurg study (RCT on the effects of different Roux-en-Y gastric bypass (RYGB) limb lengths on diabetes remission in patients with BMI ≥ 27 to ≤ 60 kg/m2 and T2DM; trial registration: DRKS00007810, German Clinical Trials Register Freiburg), 24 consecutive patients underwent liver function (LiMAx) and imaging assessments (MRI, transient elastography; TE) before and after diet and surgery. Two weeks before surgery, the patients received a hypocaloric protein-rich diet.

Nine of 18 patients had a pathologic LiMAx value (≤ 315 µg/kg/h) at baseline. After two weeks of diet, LiMAx values improved (p = 0.01, paired t test, n = 15). LiMAx values further recovered six months after RYGB (p = 0.01, paired t test, n = 15), which was accompanied by decreased liver volumes (p = 0.005, paired t test, n = 10), proton density fat fraction (p = 0.003, paired t test, n = 12), and TE measurements (p = 0.032, paired t test, n = 14). The need for medical diabetes treatment decreased from 100 to 35%.

Liver function improved after a two-week hypocaloric protein-rich diet and metabolic surgery in patients with obesity and T2DM. These data suggest that a two-week diet for this group of patients prior to abdominal surgery could improve a presumably impaired liver function.

Obesity is becoming one of the major non-communicable diseases with increasing incidence and risks that cannot be ignored. However effective and safe clinical treatment strategies still need to be deeply explored. Increased number and volume of adipocytes lead to overweight and obesity. The aim of our work is to identify lncRNAs that have important regulatory in differentiation of human mesenchymal stem cells (MSCs) into adipocytes, and to provide effective targets for clinical prevention and treatment of obesity and related metabolic disorders.

We extracted primary MSCs from human adipose tissue, and conducted expression profile analysis of lncRNAs during adipogenic differentiation of MSCs to screen changed lncRNAs. Characteristics of lncRNA were revealed mainly by RACE and RNA FISH. Loss- and gain-of function experiments in vivo and in vitro were used to analyze effects of lncRNA. Targeted metabolomics was utilized to detect levels of free fatty acids. RNA pull-down, mRNA stability tests, etc. were employed to explore mechanisms of lncRNA.

Human-specific lncRNA, we named it MEK6-AS1, was the most up-regulated transcript during adipogenic differentiation of MSCs. MEK6-AS1 was highly expressed in adipose tissue samples from individuals with BMI ≥ 25 and positively correlated with adipogenic marker genes in these samples. Knocking down lncRNA inhibited expression of adipogenic differentiation markers and ectopic adipogenesis, reducing contents of various free fatty acids, as well as promoting osteogenic differentiation. Overexpression of lncRNA had the opposite effects to the above processes. We also found that MEK6-AS1 was elevated during hepatic steatosis organoid generation. Mechanistically, MEK6-AS1 worked partially through stabilization of MEK6 mRNA by NAT10.

We have identified a human-specific lncRNA (MEK6-AS1) with position information in the genomic database but has not been extensively reported. We demonstrated that MEK6-AS1 as a novel lncRNA involved in adipogenic differentiation and adipogenesis, fatty acid metabolism, and osteogenic differentiation. We found that MEK6-AS1 may exert its effect by enhancing MEK6 mRNA stability through NAT10. Our study may provide insights into implication of lncRNAs in stem cell biology and offer a new potential therapeutic target for the prevention and treatment of obesity and other related disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition in children, underscoring the urgent need for non-invasive markers for early detection in this population.

We utilized survey data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 regarding liver ultrasound transient elastography (LUTE) for the diagnosis of NAFLD (dependent variable), and used multiple logistic regression models to explore the association between weight-adjusted waist circumference index (WWI) and the prevalence of NAFLD in US adolescents. Smoothing curves and threshold effect analyses were used to assess the non-linear association between the independent variables and the dependent variable. Subgroup analysis was conducted to pinpoint particularly susceptible subgroups within our study cohort of 1,711 participants.

Our findings indicated a positive correlation between WWI and NAFLD scores. Adjusting for all covariates revealed a significant association between increased WWI and the presence of NAFLD, with an odds ratio of 3.37 (95% CI: 2.74, 4.15). This association proved stronger than those observed with waist circumference, body mass index, and NAFLD. Stratifying WWI into quartiles showed a clear and strong positive correlation (P for trend < 0.0001). The results of smoothing curves and threshold effect analysis showed a non-linear relationship between WWI and NAFLD (LLR < 0.001). Notably, for WWI values below 10.65, a significant correlation was observed (OR = 5.25, 95% CI: 3.77,7.31). Additionally, our subgroup analysis revealed that WWI and NAFLD were associated more positively among male participants aged 16 years and older.

WWI is positively correlated with NAFLD in American adolescents and offers a straightforward and cost-effective method for identifying hepatic steatosis. The findings highlight the importance of focusing on individuals with a WWI below 10.65, where the risk of NAFLD increases. Priority should be given to the male adolescent population aged 16 and above.

Intermittent fasting (IF) can be an effective dietary therapy for weight loss and improving cardiometabolic health. However, there is scant evidence regarding the role of IF on indicators of liver function, particularly in adults with metabolic disorders. Therefore, we performed a systematic review and meta-analysis to investigate the effects of IF on liver function in adults with metabolic disorders.

Three primary electronic databases including PubMed, Web of Science, and Scopus, were searched from inception to September 2024 to identify original studies that used IF interventions with or without control groups in adults with metabolic disorders. Inclusion criteria were (1) studies of human participants with metabolic diseases, (2) interventions that evaluated the effects of IF, (3) with or without a control group, and (4) measured liver fat, liver steatosis, liver fibrosis, or liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as primary outcomes. Standardized mean differences (SMD) and 95% confidence intervals were calculated using random effects models. Heterogeneity was assessed using the Cochran's Q statistic and I-squared statistic (I2). Publication bias was assessed using the visual inspection of funnel plots and Egger's tests. The risk of bias was assessed using the PEDro scale and the NIH quality assessment tool.

A total 21 studies involving 1,226 participants with metabolic disorders were included in the meta-analysis. Overall, IF effectively decreased liver fat with a large effect size [SMD: -1.22 (95% CI: -1.63 to -0.80), p = 0.001], liver steatosis with a medium effect size [SMD: -0.73 (95% CI: -1.12 to -0.35), p = 0.001], ALT with a small effect size [SMD: -0.44 (95% CI: -0.58 to -0.30), p = 0.001], and AST with a small effect size [SMD: -0.30 (95% CI: -0.49 to -0.11), p = 0.001], but not liver fibrosis [SMD: -0.28 (95% CI: -0.59 to 0.02), p = 0.07]. Subgroup analyses showed that IF decreased liver fat and ALT significantly, independent of IF mode, participant age, health status, weight status, and intervention duration. IF significantly decreased liver fibrosis in those with obesity; and decreased AST following 5:2 diets, in middle-aged adults, adults with obesity, and regardless of health status or intervention duration.

IF seems to be an effective dietary therapy for improving liver function in adults with metabolic disorders, and many of liver function-related benefits occur regardless of IF mode, intervention duration, or participant health status.

Significant heterogeneity, small numbers of studies and inclusion of non-randomized trials or single-group pre-post trials were the main limitation of our meta-analysis. Further randomized clinical trials are needed to elucidate the effects of IF on liver function in adults with metabolic disorders.

The connections between sarcopenia and various chronic conditions, including type 2 diabetes (T2DM), metabolic syndrome (MetS), and liver disease have been highlighted recently. There is also a high occurrence of sarcopenia in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, who are often disregarded. Both experimental and clinical findings suggest a complex, bidirectional relationship between MASLD and sarcopenia. While vitamin D, testosterone, and specific drug therapies show promise in mitigating sarcopenia, consensus on effective treatments is lacking. Recent focus on lifestyle interventions emphasizes dietary therapy and exercise for sarcopenic obesity in MASLD. Challenges arise as weight loss, a primary MASLD treatment, may lead to muscle mass reduction. The therapeutic approach to sarcopenia in morbidly obese MASLD patients also includes bariatric surgery (BS). BS induces weight loss and stabilizes metabolic imbalances, but its impact on sarcopenia is nuanced, underscoring the need for further research. Our aim is to provide a comprehensive review of the interplay between sarcopenia and MASLD and offer insight into the most recent therapeutic challenges and discoveries, as sarcopenia is often overlooked or unrecognized and poses significant challenges for managing these patients.

The associations between Chinese visceral adiposity index (CVAI) and non-alcoholic fatty liver disease (NAFLD) or hepatic fibrosis in Westerners are not obvious. Furthermore, metabolic dysfunction-associated steatotic liver disease (MASLD) is the new nomenclature of NAFLD, with significantly different diagnostic criteria. The present study aimed to investigate the relationships between CVAI and MASLD or hepatic fibrosis in an American population, as well as to assess the diagnostic value of CVAI for MASLD and fibrosis.

After excluding missing data on calculations of indices, diagnosis of MASLD, and covariates, 3242 participants were selected from the National Health and Nutrition Examination Survey 2017-2020. Multivariate logistic regression analyses and restricted cubic spline (RCS) were used to determine the associations between CVAI and MASLD or fibrosis. The diagnostic capacity was evaluated by the area under the receiver operating characteristic (AUROC) curve. Data were analyzed using R software (version 4.2.2). P<0.05 was considered statistically significant.

The risk of MASLD was increased at quartiles 2, 3, and 4 compared with quartile 1 of CVAI (OR [95% CI]=3.66 [2.44-5.63], 7.954 [5.31-12.23], and 14.84 [9.80-23.06], respectively), (P<0.001). The odds ratios (95% CI) of hepatic fibrosis risk were 1.23 [0.67, 2.30], 2.44 [1.39, 4.43], 7.46 [4.36, 13.30] for the quartiles 2, 3, and 4 compared to the lowest quartile (P<0.001). According to RCS, CVAI, MASLD, and fibrosis, all had positive relationships. CVAI had AUROCs of 0.759 and 0.771 for diagnosing MASLD and fibrosis, respectively.

The CVAI was positively related to the risk of MASLD or liver fibrosis and could be a novel biomarker for predicting MASLD and fibrosis in the American population.

Nonalcoholic fatty liver disease (NAFLD) and its development into nonalcoholic steatohepatitis (NASH) are challenging health concerns globally. Clinically, the prevalence and severity of NAFLD/NASH are higher in men than in premenopausal women. NAFLD is strongly correlated with obesity, both of which are tied to high-fat/fructose-rich western diets. Therefore, we aimed to investigate sexual dimorphism in NAFLD pathogenesis in male and female C57BL/6 mice fed different diets. Male and female C57BL/67 mice were divided into four groups and kept on a chow (C), chow plus high fructose (CF), high fat (HF), and high fat plus high fructose (HFF) diet for 22 weeks. Liver tissues were collected at the end of the study and processed for NAFLD/NASH-related histology (H&E and trichrome staining), protein expression (SREBP1, SCAP, FABP4, α-SMA, TGF-β and L-PGDS), and biochemical parameters measurement. Our results displayed that female mice exhibited protection against NAFLD and diabesity on HF and HFF diets compared to male mice fed similar diets. Additionally, female mice showed protection from fibrosis compared to male mice. Both male and female mice fed HF and HFF diet groups displayed the cytosol-to-nuclear translocation of Lipocalin Prostaglandin D2 Synthase (L-PGDS). Cytoplasmic levels of L-PGDS were absent in females compared to low levels in males, revealing a possible sex-specific mechanism tied to fructose and fat metabolism. Collectively, female mice showed protection against NAFLD and diabesity relative to male mice, accompanied by differential regulation of hepatic lipocalin prostaglandin D2 synthase.

Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as "silent pandemic", this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with incident cardiovascular disease (CVD). However, CVD risk could vary across and within individuals with MASLD. We investigated the cardiovascular implications of MASLD, cardiometabolic risk factor count, and their longitudinal changes.

From nationwide health screening data, we included adults aged 20-79 years without increased/excessive alcohol intake, concomitant liver diseases, and prior CVD at baseline examination in 2009 (N = 7,292,497). Participants were classified according to MASLD status; those with MASLD were further categorized by their count of qualifying cardiometabolic risk factors (1-5). Individuals who underwent follow-up examinations in 2011 (N = 4,198,672) were additionally classified according to their baseline and follow-up MASLD status; those with persistent MASLD were further categorized by combination of baseline and follow-up cardiometabolic risk factor counts. The risk of incident CVD was assessed using multivariable-adjusted Cox model.

Over a median follow-up of 12.3 years, 220,088 new CVD events occurred. The presence of MASLD was associated with higher incidence of CVD. Among participants with MASLD, the risk of CVD increased gradually with higher cardiometabolic risk factor count (per 1-higher; hazard ratio [HR] 1.18, 95% confidence interval [CI] 1.18-1.19). The development of MASLD during follow-up was associated with higher risk of CVD (HR 1.28, 95% CI 1.25-1.31), whereas the regression of MASLD was associated with lower risk of CVD (HR 0.84, 95% CI 0.82-0.86). Among individuals with persistent MASLD, gaining and losing cardiometabolic risk factor count during follow-up were associated with elevated and reduced risk of CVD, respectively.

MASLD status, cardiometabolic risk factor count, and their longitudinal changes were all associated with the risk of incident CVD. Accurate identification of these markers may facilitate personalized management of MASLD-related CVD risk.

MicroRNAs play a pivotal role in the regulation of adipose tissue function and have emerged as promising therapeutic candidates for the management of obesity and associated comorbidities. Among them, miR-1 could be a potential biomarker for metabolic diseases and contribute to metabolic homeostasis. However, thorough research is required to fully elucidate the impact of miR-1 on human adipocyte thermogenesis and metabolism. This study aimed to explore the effect of miR-1 on human adipocyte browning, a process whose activation has been linked to obesity protection and counteraction. Human multipotent adipose-derived stem cells, hMADS cells, were differentiated into white and brown-like adipocytes and transfected with miR-1 mimics for gene expression and western blotting analyses. miR-1 inhibited the expression of its previously validated target PTK9/TWF1 and modulated the expression profile of key genes involved in thermogenesis and adipocyte browning (increased UCP1 at mRNA and protein level, increased CPT1M, decreased HIF3A), adipocyte differentiation and metabolism (decreased PLIN1, FASN, RXRA, PPARG, FABP4, MAPKAPK2), as well as genes related to the cytoskeleton (decreased ACTB) and extracellular matrix (decreased COL1A1). These findings suggest that miR-1 can modulate the expression of adipocyte human genes associated with thermogenesis and metabolism, which could hold value for eventual therapeutic potential in obesity.