NAFLD is a global and complex liver disease caused by multiple factors. Intrahepatocellular steatosis is the primary prerequisite for the occurrence and development of NAFLD. It has been shown that miR-125b-5p is highly correlated with NAFLD, and ESRRA is a factor that regulates lipid metabolism. The purpose of our study is to investigate whether miR-125b-5p regulates FFA-induced steatosis in L02 cells by targeting ESRRA.

Estrogen-related receptor alpha (ESRRA) was identified as a direct target of miR-125b-5p through database prediction and a dual-luciferase reporter gene assay. L02 cells were induced with free fatty acids (OA:PA, 2:1) at concentrations of 0.3 mM, 0.6 mM, 0.9 mM, 1.2 mM and 1.5 mM for 24 h, 48 h and 72 h, respectively. The degree of hepatocyte steatosis and triglyceride content were separately manifested by oil red O staining and colorimetric method. Cell viability per group was detected by CCK-8 assay. Eventually, 0.9 mM and 24 h were screened out as the optimal concentration and time for establishing the in-vitro model of hepatic steatosis. Followingly, miR-125b-5p and ESRRA were knocked down by transient transfection. We monitored the expressions of lipid metabolism factors SREBP-1c, ACC1 and FAS and determine triglyceride content within the cells per group. The data showed that knockdown of ESRRA led to down-regulation of the expressions of SREBP-1, ACC1, FAS and triglyceride content. Meanwhile, knockdown of ESRRA and miR-125b-5p resulted that the expressions of ESRRA, SREBP-1, ACC1, FAS and triglyceride content rebounded.

MiR-125b-5p down-regulates the expressions of lipid metabolism-related factors by negatively regulating ESRRA, thereby improving hepatic steatosis.

In addition to histological evaluation for nonalcoholic fatty liver disease (NAFLD), a comprehensive analysis of the metabolic landscape is urgently needed to categorize patients into distinct subgroups for precise treatment. In this study, a total of 806 NAFLD and 267 normal liver samples were comprehensively analyzed. Alterations in 114 metabolic pathways were investigated and two distinct metabolic clusters were identified. Single-cell RNA sequencing (scRNA-seq) analysis was utilized to decipher the metabolic activities within the microenvironment of NAFLD-derived liver cirrhosis. A refined fibrosis prediction model was developed using a Gaussian Mixture Model (GMM), demonstrating superior performance in fibrosis discrimination across multiple independent cohorts. Additionally, using The Cancer Genome Atlas (TCGA), CACNB1 protein was identified as a promising therapeutic target for hepatocellular carcinoma (HCC) patients with elevated metabolic dysfunction scores (MBDS). Machine learning algorithms were applied to MBDS-related genes to select an optimal prognostic model for HCC. All the models were trained in an HCC cohort obtained from the Gene Expression Omnibus (GEO), and the best model was validated in two independent HCC datasets: the TCGA-HCC cohort and LIRI-JP cohort. Overall, we provide insights of metabolic molecular subtyping and its potential clinical applicability in risk stratification for NAFLD and HCC individuals.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent, multifactorial systemic metabolic disorder, now recognized as the most common chronic liver disease globally. Female susceptibility to MASLD varies across menstrual states, influenced by genetic factors, age, menopausal status, and physical activity. Postmenopausal women, experiencing a significant reduction in estrogen, are particularly vulnerable to metabolic imbalances, increasing their risk of MASLD, disease progression, liver fibrosis, insulin resistance, and adverse cardiovascular events compared to premenopausal women and age-matched men. This review systematically synthesizes current research on extrahepatic abnormalities associated with MASLD in postmenopausal women. This review identifies key extrahepatic markers associated with MASLD in postmenopausal women, highlighting gaps in current research and proposing targeted screening and management strategies. (Graphical Abstract).

Highly accurate and sensitive measurements of fatty acids (FAs) in biological samples are essential for advancing our understanding of their diverse biofunctions. In this work, based on the characteristic isotope pattern of iridium (191/193Ir), we employed an iridium-encoded amine (Ir-NH2) as the derivatization reagent to establish a selective and sensitive liquid chromatography-mass spectrometry (LC-MS) method for rapid identification and accurate quantification of FAs in biological samples. Upon derivatization, nonvolatile FAs were transformed into amide derivatives tagged with a charged iridium tag, exhibiting improved sensitivity and selectivity in the electrospray ionization (ESI) positive ion mode. By leveraging the unique 2.002 Da mass shift and the 3:5 peak intensity ratio from the natural 191Ir and 193Ir isotopes, we can rapidly and efficiently screen the potential carboxyl-containing metabolites from biological samples. Compared to other existing methods, our technique offers higher sensitivity, better signal-to-noise ratio, lower detection limit (1.2-8.4 pg/mL), and easier quantification due to the clear identification of iridium-tagged derivatives. With this method, a total of 58 FAs, including both saturated and unsaturated types, were detected in mice serum lipid extracts, with carbon chain lengths varying from C9 to C24. More importantly, this method was successfully employed for global profiling of nonvolatile serum FAs from mice with nonalcoholic fatty liver disease (NAFLD), providing a novel means for detecting them and offering new avenues for exploring their functional roles and disease associations.

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of liver disease in the US, while Rheumatoid arthritis (RA) affects a significant portion of the global population. In recent times, newer drugs have been developed to slow down the progression of RA, one of which is hydroxychloroquine (HCQ). Despite HCQ being linked to slowly progressive transaminitis, its role in the development of NASH remains unclear. Our research fills this gap by examining the prevalence and risk factors of developing NASH in patients with RA on HCQ.

This retrospective cohort study analyzed 619,350 adult patients diagnosed with RA. Data were sourced from a multicenter database covering over 360 hospitals across 26 healthcare systems in the US from 1999 to September 2022, excluding pregnant individuals. Multivariate regression analysis assessed the risk of NASH, adjusting for confounders including smoking history, male gender, dyslipidemia, hypertension, type 2 diabetes mellitus, obesity, and hydroxychloroquine use. Statistical significance was set at P<0.05, with analyses conducted using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2008).

In a cohort of 79.4 million individuals, 619,350 non-pregnant subjects had rheumatoid arthritis, with 3,080 diagnosed with NASH, while 616,270 did not. Patients with NASH displayed a higher prevalence of smoking history, hyperlipidemia, hypertension, type 2 diabetes mellitus, obesity, and HCQ use. Multivariate regression analysis identified increased NASH risk in smokers (OR: 1.24; 95%CI: 1.14-1.36), males (OR: 0.88; 95%CI: 0.81-0.96), individuals with dyslipidemia (OR: 1.34; 95%CI: 1.21-1.47), hypertension (OR: 1.11; 95%CI: 1.00-1.27), type 2 diabetes mellitus (OR: 3.24; 95%CI: 2.98-3.54), obesity (OR: 3.59; 95%CI: 3.31-3.89), and hydroxychloroquine use (OR: 1.79; 95%CI: 1.65-1.94).

RA patients on HCQ showed an increased prevalence and odds of developing NASH, even after adjusting for common confounding factors. This indicates that HCQ may play a role in the development of hepatic steatosis and fibrosis. Clinicians should consider this association to prevent advanced liver disease. Future research should focus on optimal screening for early detection and enhancing patient outcomes.

• The study investigates the relationship between nonalcoholic steatohepatitis (NASH) and rheumatoid arthritis (RA), analyzing the impact of hydroxychloroquine (HCQ) use on the development of NASH.

• HCQ slows the progression of RA; however, its effect on the liver is not yet fully understood.

• This multicenter retrospective cohort study analyzed 619,350 adult patients diagnosed with RA.

• RA patients on HCQ showed an increased prevalence and higher odds of developing NASH. This association should be considered to prevent advanced liver disease.

Metabolic syndrome is present in a subset of individuals harboring a constellation of metabolic risk factors that heightens their likelihood of developing coronary artery disease. Non-alcoholic fatty liver disease (NAFLD) manifests through the incremental accumulation of fat within liver cells in the absence of secondary causes. NAFLD has long been recognized as the hepatic manifestation of metabolic syndrome. Our study seeks to ascertain the prevalence of metabolic syndrome among NAFLD patients at King Khalid University Hospital and to explore the factors associated with metabolic syndrome.

We conducted a retrospective study targeting 1,173 patients diagnosed with NAFLD at King Khalid University Hospital in Riyadh, Saudi Arabia, from March 2020 to March 2021. NAFLD diagnosis was made based on ultrasonographic evidence of a fatty liver, excluding other liver ailments and alcohol intake. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) criteria, which require at least three of five metabolic risk factors to be present. Statistical analysis was performed using chi-square tests for categorical variables and independent t-tests for continuous variables, with a significance level set at p < 0.05.

Out of 1173 NAFLD participants evaluated, 38.2% met the NCEP/ATPIII criteria for metabolic syndrome. Additionally, 23.8% had at least one metabolic syndrome component coinciding with their ultrasonographically confirmed NAFLD diagnosis. The incidence of NAFLD was not linked to gender. Married individuals constituted a higher percentage (42.8%) of the NAFLD cohort. Elevated blood glucose and triglyceride levels, along with reduced HDL levels, were predominantly observed among the metabolic syndrome components in NAFLD patients.

A significant portion of the NAFLD patient population was concurrently affected by metabolic syndrome. There exists a marked interrelationship between NAFLD and the components of metabolic syndrome. Regular metabolic disorder screenings are recommended for this patient group.

The effects of metabolic syndrome (MetS), its individual components, and baseline liver histology, on the rates of progression and regression of nonalcoholic fatty liver disease (NAFLD), were evaluated.

We conducted a post hoc analysis of a multicenter prospective cohort study using the noninterventional registry of the Nonalcoholic Steatohepatitis Clinical Research Network (2002-2022). We included patients aged 18 years or older with biopsy-proven NAFLD. Outcomes included progression/regression of histology defined by changes in NAFLD Activity Score, nonalcoholic steatohepatitis, or fibrosis. Crude incidence rates were compared among patients with MetS vs those without using Kaplan-Meier curves and log-rank test. Cox proportional hazard models were used to estimate effects of MetS and its components on the fibrosis progression/regression.

We included 452 patients; the mean age was 51 years, one-third was male, and 85% was White. The median follow-up was 4.3 (range: 1-15.6) years. At baseline, patients with MetS, large waist circumference, and impaired glucose tolerance/diabetes had worse ballooning and fibrosis scores and a higher prevalence of definite nonalcoholic steatohepatitis than those without. MetS was not associated with fibrosis progression or regression. Impaired glucose tolerance/diabetes was associated with a higher risk of fibrosis progression (adjusted hazard ratio = 1.61; 95% confidence interval: 1.11-2.34) whereas hypertension was associated with a lower risk (adjusted hazard ratio = 0.64; 95% confidence interval: 0.43-0.96).

In the cohort of patients with NAFLD, MetS was associated with greater histological severity at baseline but was not a risk factor of disease progression or regression. Impaired glucose/diabetes was associated with a higher rate and hypertension with a lower rate of fibrosis progression.

The need for early non-invasive diagnostic tools for chronic liver fibrosis is growing, particularly in individuals with obesity, non-alcoholic fatty liver disease (NAFLD), and the metabolic syndrome (MetS) since prevalence of these conditions is increasing. This case-control study compared non-invasive liver fibrosis markers in obesity with NAFLD and MetS (NAFLD-MetS, n = 33), in obese (n = 28) and lean (n = 27) control groups. We used MRI (T1 relaxation times (T1) and liver stiffness), circulating biomarkers (CK18, PIIINP, and TIMP1), and algorithms (FIB-4 index, Forns score, FNI, and MACK3 score) to assess their potential in predicting liver fibrosis risk. We found that T1 (892 ± 81 ms vs. 818 ± 64 ms, p < 0.001), FNI (15 ± 12% vs. 9 ± 7%, p = 0.018), CK18 (166 ± 110 U/L vs. 113 ± 41 U/L, p = 0.019), and MACK3 (0.18 ± 0.15 vs. 0.05 ± 0.04, p < 0.001) were higher in the NAFLD-MetS group compared with the obese control group. Moreover, correlations were found between CK18 and FNI (r = 0.69, p < 0.001), CK18 and T1 (r = 0.41, p < 0.001), FNI and T1 (r = 0.33, p = 0.006), MACK3 and FNI (r = 0.79, p < 0.001), and MACK3 and T1 (r = 0.50, p < 0.001). We show that liver fibrosis markers are increased in obese individuals with NAFLD and MetS without clinical signs of liver fibrosis. More studies are needed to validate the use of these non-invasive biomarkers for early identification of liver fibrosis risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is designated as the main hepatic evidence of metabolic syndrome. Over the past few decades, the use of herbal medications in the treatment of MASLD has been increasingly studied due to evidence of their potential therapeutic mechanisms, wide availability, and lower side effects. This study aimed to scrutinize the effect of an oligosaccharide isolated from Rosa canina on high-cholesterol diet-induced MASLD rabbits. Twenty-four New Zealand rabbits were categorized into three groups (eight rabbits in each group). The first group received only the standard diet. Others received 2% cholesterol for 120 days. Then, the rabbits were treated with 20 mg/kg of an isolated oligosaccharide daily by gavage for 60 days or 6 mg/kg of simvastatin as a standard. After 14-16 h of starvation, blood samples were collected to measure lipid profile and liver enzymes. In addition, histological sampling of the liver and thoracic aorta was done. Cholesterol and triglyceride were significantly decreased in the oligosaccharide-treated group (p < 0.05). Also, the activity of alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase decreased significantly. Lactate dehydrogenase activity was also decreased. Based on histopathological studies, the treatment with an isolated oligosaccharide prevented atherosclerotic changes and decreased liver injury. Our data suggest that an oligosaccharide isolated from Rosa canina possesses hypolipidemic and hepatoprotective activities which will be beneficial in MASLD.

The transcription factor carbohydrate response element binding protein (ChREBP) has emerged as a crucial regulator of hepatic glucose and lipid metabolism. The increased ChREBP activity involves the pro-oncogenic PI3K/AKT/mTOR signaling pathway that induces aberrant lipogenesis, thereby promoting hepatocellular carcinomas (HCC). However, the molecular pathogenesis of ChREBP-related hepatocarcinogenesis remains unexplored in the high-fat diet (HFD)-induced mouse model. Male C57BL/6J (WT) and liver-specific (L)-ChREBP-KO mice were maintained on either a HFD or a control diet for 12, 24, and 48 weeks, starting at the age of 4 weeks. At the end of the feeding period, mice were perfused, and liver tissues were formalin-fixed, paraffin-embedded, sectioned, and stained for histological and immunohistochemical analysis. Biochemical and gene expression analysis were conducted using serum and frozen liver tissue. Mice fed with HFD showed a significant increase (p < 0.05) in body weight from 8 weeks onwards compared to the control. WT and L-ChREBP-KO mice also demonstrated a significant increase (p < 0.05) in liver-to-body weight ratio in the 48-week HFD group. HFD mice exhibited a gradual rise in hepatic lipid accumulation over time, with 24-week mice showing a 20-30% increase in fat content, which further advanced to 80-100% fat accumulation at 48 weeks. Both dietary source and the increased expression of lipogenic pathways at transcriptional and protein levels induced steatosis and steatohepatitis in the HFD group. Moreover, WT mice on a HFD exhibited markedly higher inflammation compared to the L-ChREBP-KO mice. The enhanced lipogenesis, glycolysis, persistent inflammation, and activation of the AKT/mTOR pathway collectively resulted in significant metabolic disturbances, thereby promoting HCC development and progression in WT mice. In contrast, hepatic loss of ChREBP resulted in reduced hepatocyte proliferation in the HFD group, which significantly contributed to the impaired hepatocarcinogenesis and a reduced HCC occurrence in the L-ChREBP-KO mice. Our present study implicates that prolonged HFD feeding contributes to NAFLD/NASH, which in turn progresses to HCC development in WT mice. Collectively, hepatic ChREBP deletion ameliorates hepatic inflammation and metabolic alterations, thereby impairing NASH-driven hepatocarcinogenesis.

Obesity among the young is an emerging health problem with many metabolic changes including liver damage. Our objective was to investigate the association of fatty liver with serum uric acid (UA) and gamma-glutamyltransferase (GGT) in a cohort of obese children in Sri Lanka.

A cross-sectional analytical study was conducted among 5-15-year-old obese children (based on WHO 2007 standards). After a 12-hour overnight fast, blood was drawn for glucose, lipid profile, alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin, UA and GGT. Height, weight, waist circumference, blood pressure and fat mass were measured. Ultrasound scan of abdomen was performed to determine fatty liver.

We studied 146 obese children with a mean age (SD) 9.86 (2.1) years. The fatty liver group showed significantly elevated levels (p < 0.05) of UA, oral glucose tolerance test (OGTT), triglycerides (TG), AST, ALT, GGT, insulin resistance (HOMA-IR) and a reduced AST/ALT ratio, compared to the non-fatty liver group. Chi square test showed statistically significant associations between fatty liver and AST, ALT, AST/ALT ratio, HOMA-IR, UA and GGT. With existing cut offs, GGT (> 30 U/L) and UA (> 330 µmol/L) the sensitivity and specificity of GGT in predicting fatty liver was 26.9% and 94.1% respectively while for UA it was 38.5% and 83.8% respectively. A cut-off value of 18.5 U/L (sensitivity 76.9% and specificity 52.9%) for GGT, 277µmol/L (sensitivity 70.5% and specificity 57.4%) for UA, 27.5 U/L (sensitivity 70.5%, specificity 51.5%) for AST, 21.5 U/L (sensitivity 80.8% and specificity 61.8%) for ALT, a ratio of 0.99 (sensitivity 77.9% and specificity 55.1%) for AST/ALT and 2.02 (sensitivity 73.2%, specificity 58.5%) for HOMA-IR predicted fatty liver.

GGT and UA are associated with fatty liver and these biomarkers can be used to predict fatty liver disease.

Steatotic liver disease is prevalent among people with hepatitis C virus (HCV). The new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasises the metabolic drivers of steatosis and recognises its frequent coexistence with other chronic liver diseases, including HCV. We aimed to evaluate the association of coexisting MASLD and HCV with liver fibrosis. Individuals with HCV who underwent transient elastography (TE) with associated controlled attenuation parameter (CAP) were included from two clinical centres. MASLD and significant liver fibrosis were defined as the presence of steatosis (CAP ≥ 275 dB/m) with at least one cardiometabolic risk factor, and liver stiffness measurement (LSM) ≥ 7.1 kPa measured by TE, respectively. Associated cofactors of significant liver fibrosis were determined using stepwise regression and cross-validation by LASSO models to select confounders. Among 590 participants, 31% were diagnosed with MASLD. The prevalence of significant liver fibrosis was the highest among people with MASLD (58%) followed by HCV-related steatosis (45%) and the non-steatosis group (39%). After adjusting for potential confounders, MASLD was associated with significant liver fibrosis (adjusted odds ratio [aOR] 2.29, 95% confidence interval [CI] 1.07-4.87). Furthermore, specific MASLD phenotypes including diabetes, hypertension and overweight were associated with significant liver fibrosis, with aORs of 4.76 (95% CI 2.16-10.49), 3.44 (95% CI 1.77-6.68) and 2.54 (95% CI 1.27-5.07), respectively. In conclusion, MASLD is associated with liver fibrosis in people with HCV, specifically the diabetes, overweight and hypertensive phenotypes. Beyond pursuing a virological cure, healthcare providers should prioritise managing metabolic conditions, particularly diabetes, hypertension and obesity.

Statins are used for metabolic dysfunction-associated steatotic liver disease (MASLD) (NAFLD) treatment, but their role in this context is unclear. Genetic variants of patatin-like phospholipase domain containing 3 (PNPLA3) are associated with MASLD susceptibility and statin treatment efficacy. Access to liver biopsies before established MASLD is limited, and statins and PNPLA3 in early liver steatosis are thus difficult to study.

Liver biopsies were collected from 261 patients without known liver disease at surgery and stratified based on statin use and criteria for the metabolic syndrome (MS). Genotypes and transcript levels were measured using Illumina and Affymetrix arrays, and metabolic and lipoprotein profiles by clinical assays. Statin effects on PNPLA3, de novo lipogenesis (DNL), and lipid accumulation were further studied in vitro.

The PNPLA3I148M genetic variant was associated with significantly lower hepatic levels of cholesterol synthesis-associated transcripts. Patients with MS had significantly higher hepatic levels of MASLD and lipogenesis-associated transcripts than non-MS patients. Patients with MS on statin therapy had significantly higher hepatic levels of PNPLA3, acetyl-CoA carboxylase alpha, and ATP citrate lyase, and statin use was associated with higher plasma fasting glucose, insulin, and HbA1c. Exposure of hepatocyte-like HepG2 cells to atorvastatin promoted intracellular accumulation of triglycerides and lipogenesis-associated transcripts. Atorvastatin-exposure of HepG2, sterol O-acyltransferase (SOAT) 2-only-HepG2, primary human hepatic stellate, and hepatic stellate cell-like LX2 cells significantly increased levels of PNPLA3 and SREBF2-target genes, whereas knockdown of SREBF2 attenuated this effect.

Collectively, these observations suggest statin-associated regulation of PNPLA3 and DNL in liver. The potential interaction between PNPLA3 genotype and metabolic status should be considered in future studies in the context of statin therapy for MASLD.

Stimulator of interferon genes (STING) is positively correlated with the degrees of liver inflammation in human metabolic dysfunction-associated steatotic liver disease (MASLD). In addition, STING disruption alleviates MASLD in mice fed a high-fat diet (HFD) for 3 months (3-m-HFD). Here we investigated the role of the duration of dietary feeding in regulating MASLD in mice and explored the involvement of STING in sex differences in MASLD. Both male and female STING-disrupted (STINGgt) and wild-type C57BL/6J mice were fed an HFD for 3 or 7 months (7-m-HFD). Additionally, female STINGgt mice upon ovariectomy (OVX) and 3-m-HFD were analyzed for MASLD. Upon 3-m-HFD, STINGgt mice exhibited decreased severity of MASLD compared to control. However, upon 7-m-HFD, STINGgt mice were comparable with wild-type mice in body weight, fat mass, and MASLD. Regarding regulating the liver RNA transcriptome, 7-m-HFD increased the expression of genes indicating proinflammatory activation of various liver cells. Interestingly, the severity of MASLD in female mice was much lighter than in male mice, regardless of STING disruption. Upon OVX, female STINGgt mice showed significantly increased severity of MASLD relative to sham control but were comparable with male STINGgt mice. Upon treatment with 17-beta estradiol (E2), hepatocytes revealed decreased fat deposition while macrophages displayed decreases in lipopolysaccharide-induced phosphorylation of Nfkb p65 and Jnk p46 independent of STING. These results suggest that 7-m-HFD, without altering female sex-based protection, abolishes STING disruption-driven protection of MASLD, likely through causing proinflammatory activation of multiple types of liver cells to offset the effect of STING disruption.

Background/Objectives: An increasing number of studies have reported liver involvement in both children and adults with celiac disease (CD). This often manifests as isolated hypertransaminasemia or hepatic steatosis (HS). The aim of this study was to define the prevalence of hypertransaminasemia and HS in a pediatric population with CD before starting a gluten-free diet (GFD) and to analyze how the introduction of a GFD could modify this condition. We also conducted a state-of-the-art literature review of the association between hypertransaminasemia, metabolic dysfunction-associated steatotic liver disease (MASLD) and CD. Methods: We retrospectively reviewed the clinical charts of pediatric CD patients diagnosed in three different pediatric units of Sicily, analyzing clinical, laboratory, ultrasound, and histology data before and 12 months after the introduction of a GFD. Results: A total of 160 patients (65.0% females, median age 6.4 (0.8-13.2) years) were included; hypertransaminasemia and HS prevalences at diagnosis were 8.1% and 6.1%, respectively. Subjects with hypertransaminasemia were younger (p = 0.01) than those without and had higher frequencies of HS (p = 0.034) and anti-tissue transglutaminase (tTg) immunoglobulin (Ig)G positivity (p = 0.046). Subjects with HS were younger (p = 0.0001) and had a higher frequency of hypertransaminasemia (p = 0.029) compared to non-steatotic ones. After 12 months of a GFD, hypertransaminasemia and HS persisted in 53.8% and 50.0% of patients, respectively. Conclusions: The prevalences of hypertransaminasemia and HS in Sicilian pediatric CD patients seem to be lower than those reported in other geographical areas. A GFD can reverse the trend of liver involvement, although periods of longer than 12 months may be necessary. However, a GFD has been associated with an increased prevalence of HS, and so regular follow-up involving a nutritionist should be recommended to guide physicians in patient management.

There are few descriptions of the epidemiology of chronic liver disease (CLD) after allogeneic hematopoietic stem cell transplantation (allo-HCT). Among those transplanted before 2000, viral hepatitis was the dominant cause of CLD. Recently, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD, previously known as nonalcoholic fatty liver disease) is increasing in the general population. In addition, survivors of allo-HCT are known to be at increased risk of metabolic syndrome. We set out to describe the epidemiology of CLD in a modern cohort of allo-HCT recipients. We hypothesized that MASLD would be the most common cause of CLD in the cohort.

We undertook a retrospective cohort and nested case-control study of 2-year survivors of allo-HCT in Alberta transplanted between 2008 and 2018.

Among 392 2-year survivors of allo-HCT between 2008 and 2018, the prevalence of CLD was 41.8% and MASLD was identified in 56% of those with CLD, followed by iron overload in 47% of those with CLD. The prevalence of MASLD among the entire cohort was 46%. Although most patients developed CLD before 2 years post-transplant, there was a 13% cumulative incidence of new CLD after 2 years posttransplant. Grade 2-4 acute graft-versus-host disease and/or moderate-to-severe chronic graft-versus-host disease and pretransplant CLD were strongly associated with CLD. In the case-control study examining the association between cardiovascular risk factors and CLD, type 2 diabetes was associated with CLD. Cirrhosis developed in 1.5% of survivors, and MASLD was an underlying etiology in one half of these cases. There was no difference in overall survival and non-relapse mortality between those who did and did not develop CLD.

MASLD is the main cause of CLD in recent long-term survivors of allo-HCT and may be associated with post-transplant corticosteroid exposure and type 2 diabetes. We note a shift in the underlying etiology of CLD post-HCT: previous studies describe viral hepatitis as the most common cause of CLD. The high prevalence of MASLD in allo-HCT recipients has important implications for survivorship care.

The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease and those with metabolic dysfunction and alcohol-associated liver disease remain unclear.

To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases.

This observational cohort study included 1866 patients with metabolic dysfunction-associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol-associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non-invasive liver fibrosis scores were assessed using the Cox regression analysis.

Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol-associated liver disease than with metabolic dysfunction-associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction-associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor.

Although both metabolic steatotic liver disease and metabolic alcohol-associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction-associated steatotic liver disease.

To explore any correlation between serum urate (SU) level or insulin resistance (IR) and metabolic dysfunction associated steatotic liver disease (MASLD) in patients with metabolic syndrome (MS).

Data from all MASLD patients, diagnosed by liver biopsy, were enrolled and divided into MASLD alone group and MASLD with MS group. They were subdivided into hyperuricemia group and normal SU group to find correlation between SU/IR and MASLD in patients with MS and independent risk factors for MASLD.

Data from 539 MASLD patients were analyzed. Body mass index (BMI) (p = 0.000), waist circumference (WC) (p = 0.004), and low-density lipoprotein (LDL) (p = 0.000) were dramatically higher in MASLD with MS group than those with MASLD alone; MASLD with MS patients had significantly more family history of diabetes (p = 0.000) and hypertension (p = 0.000) than patients with MASLD alone. Height (p = 0.000), weight (p = 0.000), BMI (p = 0.000) and WC (p = 0.001), and LDL (p = 0.007) were dramatically higher in hyperuricemia patients than those with normal SU. SU was inversely associated with age (p = 0.000) and high-density lipoprotein (HDL) (p = 0.003), and positively correlated with weight (p = 0.000), BMI (p = 0.000) and WC (p = 0.000), TG (p = 0.000), and LDL (p = 0.000). Logistic Regression analysis showed that age (p = 0.031), TG (p = 0.002), LDL (p = 0.010), HbA1c (p = 0.026), and family history of hypertension (p = 0.000) may be independent risk factors for MASLD in patient with MS.

Insulin resistance (IR) in MASLD patients with MS, but not higher SU levels, has closer correlation with the occurrence of MASLD in patients with family history of hypertension and diabetes having higher BMI, LDL, HbA1c.

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.

The identification of biomarkers for the early diagnosis of nonalcoholic fatty liver disease (NAFLD) is urgently needed. Here, we aimed to identify NAFLD biomarkers in the early stages of steatosis (SS) and nonalcoholic steatohepatitis (NASH) based on differential gene expression from bioinformatics data.

A meta-analysis was performed from transcriptomic databases retrieved from public repositories containing data from biopsies of patients at various stages of NAFLD development. The status of the selected molecules was validated in the serum of patients with NAFLD by ELISA.

We identified 121 differentially expressed genes (DEGs) associated with SS and 402 associated with NASH. Gene Ontology (GO) enrichment revealed that the altered genes were primarily associated with dysfunction of primary cellular processes, and pathway analyses were mainly related to cholesterol metabolism. We identified ACSS2, PCSK9, and CYP7A1 as candidate biomarkers for SS and ANGPTL3, CD36, CYP51A1, FASN, FAS, FDFT1, and LSS as candidate biomarkers for NASH.

By experimental validation of bioinformatics data from patients with NAFLD, we identified promising biomarkers for detecting SS and NASH that might be useful for screening and diagnosing early NAFLD stages in humans.

This investigation seeks to explore the correlation between nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs), and to to provide evidence for the prevention and treatment of CVDs.

This study utilized data from the Jinchang cohort platform, including 19,399 participants without pre-existing major CVDs. Based on the general population and gender stratification, Cox models were used to analyze the risk of NAFLD for CVDs. The combined effect of NAFLD and different obesity indicators on CVDs was analyzed by additive and multiplicative interaction models and subgroups.

There were 3129 NAFLD patients out of 19399 subjects, and 723 (23.11%) of them had the CVD. After adjusting for multiple confounding factors, the Cox model revealed a 1.17-fold increase in the risk of CVDs among patients with NAFLD compared to those without NAFLD. Moreover, there was no notable disparity in CVDs risk among most NAFLD patients at the same level of obesity. The results indicated no additive interaction between NAFLD and obesity concerning CVDs risk, but rather a positive multiplicative interaction. Using the normal population as a reference, it was found that people with both obesity and NAFLD significantly increased the risk of developing CVDs, with HRs and 95% CIs of 1.790 (1.508, 2.126), 1.356 (1.213, 1.517), and 1.807 (1.503, 2.174), respectively, for BMI, WC, and the combination of BMI and WC.

NAFLD and obesity are independent risk factors for CVDs. The synergy of obesity and NAFLD implies that NAFLD patients should control weight gain. Larger BMI and WC values may increase the CVDs risk for NAFLD patients, especially women.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), poses a significant threat to global health. Despite extensive research efforts over the past decade, only one drug has received market approval under accelerated pathways. In this review, we summarise the pathogenesis of MASH and present a comprehensive overview of recent advances in phase 2-3 clinical trials targeting MASH. These trials have highlighted considerable challenges, including low response rates to drugs, limitations of current surrogate histological endpoints, and inadequacies in the design of MASH clinical trials, all of which hinder the progress of MASH pharmacotherapy. We also explored the potential of non-invasive tests to enhance clinical trial design. Furthermore, given the strong association between MASLD and cardiometabolic disorders, we advocate for an integrated approach to disease management to improve overall patient outcomes. Continued investigation into the mechanisms and pharmacology of combination therapies may offer valuable insights for developing innovative MASH treatments.

Circular RNAs (circRNAs) are a unique class of RNA molecules formed through back-splicing rather than linear splicing. As an emerging field in molecular biology, circRNAs have garnered significant attention due to their distinct structure and potential functional implications. A comprehensive understanding of circRNAs' functions and potential clinical applications remains elusive despite accumulating evidence of their involvement in disease pathogenesis. Recent research highlights their significant roles in various human diseases, but comprehensive reviews on their functions and applications remain scarce. This review provides an in-depth examination of circRNAs, focusing first on their involvement in non-neoplastic diseases such as respiratory, endocrine, metabolic, musculoskeletal, cardiovascular, and renal disorders. We then explore their roles in tumors, with particular emphasis on exosomal circular RNAs, which are crucial for cancer initiation, progression, and resistance to treatment. By detailing their biogenesis, functions, and impact on disease mechanisms, this review underscores the potential of circRNAs as diagnostic biomarkers and therapeutic targets. The review not only enhances our understanding of circRNAs' roles in specific diseases and tumor types but also highlights their potential as novel diagnostic and therapeutic tools, thereby paving the way for future clinical investigations and potential therapeutic interventions.

N6-methyladenosine (m6A) mRNA modification and mitochondrial function hold paramount importance in the advancement of metabolic dysfunction-associated steatotic liver disease (MASLD).

The aim of this study was to elucidate the impact of m6A on hepatic mitochondrial dysfunction and provide a novel perspective for a more comprehensive understanding of the pathogenesis of MASLD.

High-throughput screening methods were used to identify the underlying transcriptome and proteome changes in MASLD model mice. Western blotting, blue native gel electrophoresis (BNGE), dot blot, and Seahorse analyses were conducted to identify and validate the underlying regulatory mechanisms of m6A on mitochondria.

In vivo, abnormal m6A modification in MASLD was attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. In vitro, knockdown of Mettl3 inhibited hepatic oxidative phosphorylation (OXPHOS) and the mitochondrial respiratory chain (MRC), while overexpression of Mettl3 promoted these processes. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed mitochondrial OXPHOS.

In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 axis, particularly by the role of YTHDF1. Modulation of the Mettl3-m6A-YTHDF1 axis has the potential to improve mitochondrial function, alleviate MASLD symptoms, and decrease the likelihood of disease progression.

Malnutrition is a public health epidemic mainly targeting poverty-stricken people, young ones, older people, pregnant women, and individuals with metabolic disorders. Severe malnutrition is linked with several metabolic defects, such as hepatic dysfunction, hypertension, cardiovascular disease, and osteoarthritis. The proper functioning of the liver plays a crucial role in ensuring the supply of nutrients to the body. Consequently, inadequate nutrition can lead to severe periportal hepatic steatosis due to compromised mitochondrial and peroxisome functions. Reduced protein intake disrupts essential metabolic processes like the TCA cycle, oxidative phosphorylation, and β-oxidation, ultimately affecting ATP production. Furthermore, this can trigger a cascade of events, including disturbances in amino acid metabolism, iron metabolism, and gut microbiota, which activate genes involved in de novo lipogenesis, leading to the accumulation of lipids in the liver. The condition, in prolonged cases, progresses to steatohepatitis and liver fibrosis. Limited therapeutic solutions are available; however, few dietary supplements and drugs have demonstrated positive effects on the growth and health of malnourished individuals. These supplements improve parameters such as inflammatory and oxidative status, reduce triglyceride accumulation, enhance insulin sensitivity, and downregulate gene expression in hepatic lipid metabolism. This review elucidates the various mechanisms involved in malnutrition-associated steatohepatitis and provides an overview of the available approaches for treating this condition.

Observational studies have shown that non-alcoholic fatty liver disease (NAFLD) is strongly associated with metabolic dysfunction. However, there is a paucity of research on whether changes in indicators of serum metabolism contribute to the development of NAFLD. This study was conducted with 4084 participants who underwent healthy physical examinations at Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China, in 2022 and 2023. Baseline and follow-up measurements, including anthropometric data, abdominal ultrasound and blood samples were collected. The diagnosis of NAFLD was based on the 2010 Chinese Guidelines on Diagnosis and Treatment of NAFLD. Multiple logistic regression was utilized to analyze the odds ratios (ORs) for the 1-year risk of NAFLD in connection with both baseline metabolic indicators and changes in metabolic indicators observed over the course of 1 year. A total of 3425 study participants who were free of NAFLD at baseline, including 1146 men and 2279 women, were included in the final analysis. The mean age was 34.43 ± 7.20 years. Participants who developed NAFLD were older, male and had higher levels of body mass index (BMI), blood pressure, fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), free triiodothyronine (fT3), uric acid (UA), alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and lower levels of high-density lipoprotein cholesterol (HDL-C) and free thyroxine (fT4) (all P values < 0.05). The multivariable model showed that baseline BMI, diastolic blood pressure (DBP), TG, TC, HDL-C, LDL-C, UA, fT4, fT3, ALT and changes in TG, HDL-C, and UA were associated with the 1-year risk of developing NAFLD. The risk of NAFLD increased by 56% [OR 1.56, 95% Confidence Interval (CI) 1.32-1.87] and 40% (OR 1.40, 95% CI 1.19-1.64) for each standard deviation (SD) increase in altered TG values (1.01 mmol/L) and altered UA values (55 µmol/L) respectively. Conversely, for each SD (0.27 mmol/L) increase in HDL-C change, the 1-year risk of incident NAFLD was reduced by 50% (OR 0.50, 95% CI 0.40-0.62). The present study suggested that increases in TG and UA, and decreases in HDL-C, significantly increase the risk of developing NAFLD. Therefore, more attention should be paid to these factors in the management and prevention of NAFLD.

To identify factors associated with non-alcoholic fatty liver disease over a 5-year period.

Three hundred seven participants, including 165 women, with a mean age of 55.6 ± 12.0 years underwent continuous quantitative MRI of the liver using the proton-density fat fraction (PDFF). The liver's fat fractions were determined at baseline and 5 years later, and the frequency of participants who developed fatty liver disease and potential influencing factors were explored. Based on significant factors, a model was generated to predict the development of fatty liver disease.

After excluding participants with pre-existing fatty liver, the baseline PDFF of 3.1 ± 0.9% (n = 190) significantly increased to 7.67 ± 3.39% within 5 years (p < 0.001). At baseline, age (OR = 1.04, p = 0.006, CI = 1.01-1.07), BMI (OR = 1.11, p = 0.041, CI = 1.01-1.23), and waist circumference (OR = 1.05, p = 0.020, CI = 1.01-1.09) were identified as risk factors. Physical activity was negatively associated (OR = 0.43, p = 0.049, CI = 0.18-0.99). In the prediction model, age, physical activity, diabetes mellitus, diastolic blood pressure, and HDL-cholesterol remained as independent variables. Combining these risk factors to predict the development of fatty liver disease revealed an AUC of 0.7434.

Within a five-year follow-up, one-quarter of participants developed fatty liver disease influenced by the triggering factors of age, diabetes mellitus, low HDL-cholesterol, and diastolic blood pressure. Increased physical activity has a protective effect on the development of fatty liver.

Obstructive sleep apnea (OSA) syndrome and nonalcoholic fatty liver disease (NAFLD) have been shown to have a close association in previous studies, but their pathogeneses are unclear. This study explores the molecular mechanisms associated with the pathogenesis of OSA and NAFLD and identifies key predictive genes.

Using the Gene Expression Omnibus (GEO) database, we obtained gene expression profiles GSE38792 for OSA and GSE89632 for NAFLD and related clinical characteristics. Mitochondrial unfolded protein response-related genes (UPRmtRGs) were acquired by collating and collecting UPRmtRGs from the GeneCards database and relevant literature from PubMed. The differentially expressed genes (DEGs) associated with OSA and NAFLD were identified using differential expression analysis. Gene Set Enrichment Analysis (GSEA) was conducted for signaling pathway enrichment analysis of related disease genes. Based on the STRING database, protein-protein interaction (PPI) analysis was performed on differentially co-expressed genes (Co-DEGs), and the Cytoscape software (version 3.9.1) was used to visualize the PPI network model. In addition, the GeneMANIA website was used to predict and construct the functional similar genes of the selected Co-DEGs. Key predictor genes were analyzed using the receiver operating characteristic (ROC) curve.

The intersection of differentially expressed genes shared between OSA and NAFLD-related gene expression profiles with UPRmtRGs yielded four Co-DEGs: ASS1, HDAC2, SIRT3, and VEGFA. GSEA obtained the relevant enrichment signaling pathways for OSA and NAFLD. PPI network results showed that all four Co-DEGs interacted (except for ASS1 and HDAC2). Ultimately, key predictor genes were selected in the ROC curve, including HDAC2 (OSA: AUC = 0.812; NAFLD: AUC = 0.729), SIRT3 (OSA: AUC = 0.775; NAFLD: AUC = 0.750), and VEGFA (OSA: AUC = 0.812; NAFLD: AUC = 0.861) (they have a high degree of accuracy in predicting whether a subject will develop two diseases).

In this study, four co-expression differential genes for OSA and NAFLD were obtained, and they can predict the occurrence of both diseases. Transcriptional mechanisms involved in OSA and NAFLD interactions may be better understood by exploring these key genes. Simultaneously, this study provides potential diagnostic and therapeutic markers for patients with OSA and NAFLD.

Obesity has become a major global public health challenge. Studies examining the associations between different obesity patterns and the risk of nonalcoholic fatty liver disease (NAFLD) are limited. This study aimed to investigate the relationships between different obesity patterns and the risk of NAFLD in a large male population in the US.

Data from the 2017 to March 2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Liver steatosis and fibrosis were assessed with FibroScan using the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM). Steatosis was identified with a CAP value of 248 dB/m or higher. Abdominal obesity was defined by a waist circumference (WC) of 102 cm or more for males and 88 cm or more for females. Overweight was defined as a body mass index (BMI) of 24.0 kg/m2 and above. General obesity was identified with a BMI of 28.0 kg/m2 or higher. Obesity status was categorized into four types: overweight, general obesity, abdominal obesity, and combined obesity. Multivariate logistic regression, adjusting for potential confounders, was used to examine the link between obesity patterns and NAFLD risk. Subgroup analysis further explored these associations.

A total of 5,858 adults were included. After multivariable adjustment, compared to the normal weight group, the odds ratios (ORs) [95% confidence interval (CI)] for NAFLD in individuals with overweight, general obesity, abdominal obesity, and combined obesity were 6.90 [3.74-12.70], 2.84 [2.38-3.39], 3.02 [2.02-4.51], and 9.53 [7.79-11.64], respectively. Subgroup analysis showed the effect of different obesity patterns on NAFLD risk was stable among individuals with different clinical conditions. In the fully adjusted multivariate logistic regression model, WC was positively associated with NAFLD risk (OR: 1.48; 95% CI: 1.42-1.53; P < 0.001). WC also demonstrated strong discriminatory ability for NAFLD in Receiver Operating Characteristic (ROC) analysis, achieving an Area Under the Curve (AUC) of 0.802.

Different patterns of obesity are risk factors for NAFLD. An increase in WC significantly increased NAFLD risk. More attention should be paid to preventing different patterns of obesity among adults.

Non-alcoholic fatty liver disease (NAFLD), which is a prevalent hepatic condition worldwide, is expected to develop into the leading reason for end-stage fatty liver in the forthcoming decades. Incorporating rapeseed oil into a balanced diet may be beneficial in improving NAFLD. The goal of this trial was to evaluate the impact of substituting ghee with rapeseed oil on primary outcomes such as fatty liver and liver enzymes, as well as on secondary outcomes including glycaemic variables, lipid profile and anthropometric measurements in individuals with NAFLD. Over 12 weeks, 110 patients (seventy men and forty women; BMI (mean) 28·2 (sd 1·6 kg/m2); mean age 42 (sd 9·6) years), who daily consumed ghee, were assigned to the intervention or control group through random allocation. The intervention group was advised to substitute ghee with rapeseed oil in the same amount. The control group continued the consumption of ghee and was instructed to adhere to a healthy diet. Results showed a significant reduction in the steatosis in the intervention group in comparison with the control group (P < 0·001). However, a significant change in the levels of alanine aminotransferase (–14·4 μg/l), γ-glutamyl transferase (–1·8 μg/l), TAG (–39·7 mg/dl), total cholesterol (–17·2 mg/dl), LDL (–7·5 mg/dl), fasting blood glucose (–7·5 mg/dl), insulin (–3·05 mU/l), Homeostatic Model Assessment for Insulin Resistance (–0·9), Quantitative Insulin-Sensitivity Check Index (+0·01), weight (–4·3 kg), BMI (–0·04 kg/m2), waist (–5·6 cm) and waist:height ratio (–0·04) was seen in the intervention group. The consumption of rapeseed oil instead of ghee caused improvements in liver steatosis and enzymes, glycaemic variables and anthropometric measurements among individuals with NAFLD.

This study aims to investigate the relationship between Sodium Glucose Co-transporter-2 inhibitors (SGLT2i) treatment and fibrosis in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD) combined with Type 2 Diabetes Mellitus (T2DM) and Major Adverse Cardiovascular and Cerebrovascular Events (MACCEs).

A case-control study was conducted, involving 280 patients with MASLD combined with T2DM treated at the First Affiliated Hospital of Xinjiang Medical University from January 2014 to October 2023. Among these patients, 135 received SGLT2i treatment. The association between the Fibrosis-4 (FIB-4) index and the occurrence of MACCEs, as well as the association between the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores and MACCEs, were evaluated.

The FIB-4 index and APRI scores were significantly lower in the SGLT2i treatment group compared to the non-SGLT2i group (1.59 vs 1.25, P<0.001). SGLT2i treatment tended to reduce the occurrence of MACCEs compared to non-SGLT2i treatment (45.5% vs 38.5%, P=0.28). All patients who developed MACCEs in the non-SGLT2i treatment group had higher FIB-4 index (1.83 vs 1.35, P=0.003). Additionally, after SGLT2i treatment for a median duration of 22 months, patients showed significant reductions in blood glucose, APRI, and FIB-4 index.

SGLT2i treatment significantly reduces the occurrence of MACCEs and liver fibrosis in patients with MASLD combined with T2DM. The FIB-4 index may serve as a potential surrogate marker for predicting the occurrence of MACCEs.

Chronic feeding of a high fat diet (HFD) in preclinical species induces broad metabolic dysfunction characterized by body weight gain, hyperinsulinemia, dyslipidemia and impaired insulin sensitivity. The plasma lipidome is not well characterized in dogs with HFD-induced metabolic dysfunction. We therefore aimed to describe the alterations that occur in the plasma lipid composition of dogs that are fed a HFD and examine the association of these changes with the clinical signs of metabolic dysfunction. Dogs were fed a normal diet (ND) or HFD for 12 weeks. Insulin sensitivity (SI) and beta cell compensation (AIRG) were assessed through an intravenous glucose tolerance test (IVGTT) and serum biochemistry was analyzed before the introduction of HFD and again after 12 weeks of continued ND or HFD feeding. Plasma lipidomics were conducted prior to the introduction of HFD and again at week 8 in both ND and HFD-fed dogs. 12 weeks of HFD feeding resulted in impaired insulin sensitivity and increased beta cell compensation measured by SI (ND mean: 11.5 [mU/l]-1 min-1, HFD mean: 4.7 [mU/l]-1 min-1) and AIRG (ND mean: 167.0 [mU/l]min, HFD mean: 260.2 [mU/l]min), respectively, compared to dogs fed ND over the same duration. Chronic HFD feeding increased concentrations of plasma lipid species and deleterious fatty acids compared to dogs fed a ND. Saturated fatty acid (SFA) concentrations were significantly associated with fasting insulin (R2 = 0.29), SI (R2 = 0.49) and AIRG (R2 = 0.37) in all dogs after 12 weeks, irrespective of diet. Our results demonstrate that chronic HFD feeding leads to significant changes in plasma lipid composition and fatty acid concentrations associated with metabolic dysfunction. High SFA concentrations may be predictive of deteriorated insulin sensitivity in dogs.