Secondary metabolites in plants of the same species, though originating from distinct geographical regions, frequently display both similarities and notable variations. A prior study on the vulnerable Chinese endemic conifer Keteleeria fortunei, collected from Yunnan province (KFYN), led to the isolation of fortunefuroic acids (FFAs) A-I. These compounds represent a unique class of triterpenoids characterized by a rare furoic acid moiety within the lateral chain. The distinct 23,27-epoxy-23,25(27)-dien-26-oic acid unit present in FFAs can be readily identified by characteristic proton NMR signals (δH-24: ca 6.36 ppm; δH-27: ca 7.97 ppm), a prominent ion fragment at m/z 125 in the EI-MS, and typical UV absorption peak around λmax 245 nm. In this study, an integrated approach was employed to dereplicate and isolate FFA-type compounds from K. fortunei collected from Fujian Province (KFFJ). This approach combined NMR, EI-MS, and LC-PDA-ESIMS data to detect and analyze compounds with molecular weights in the range of 464-468 Da, a distinguishing feature of FFA-type compounds. Consequently, six previously undescribed FFAs K-P (1-6) were obtained, alongside the re-isolation of FFAs A-D and H. Compound 1 exhibits a rare 17,14-friedo-cyclaorane type skeleton, while compound 2 is characterized as a 3,4-seco-cyclaorane-3,26-dioic acid. Compounds 3-6 are identified as derivatives of 9βH-lanost-26-oic FFAs. Additionally, a previously unreported lanost-26-oic acid derivative (7) was also identified, exhibiting an inhibitory effect on ATP-citrate lyase. Their chemical structures and absolute configurations were determined through spectroscopic analysis, GIAO NMR calculations combined with DP4+ probability analyses, and electronic circular dichroism calculations. The isolated FFAs have the potential to serve as chemotaxonomic markers for the genus Keteleeria within the Pinaceae family. This study marks the first application of integrated NMR/EI-MS/LC-PDA-ESIMS methods for both dereplication and the discovery of new natural products. Notably, the KFFJ samples were collected from a location approximately 1500 km away from that of KFYN. Understanding the impact of geographical origins on specialized metabolites may provide valuable insights into the sustainable utilization and conservation of endangered plant species.

Interactions between the liver and pancreas are key features of the carbohydrate and lipid homeostasis in healthy and pathological patients. To investigate the crosstalk between the two organs, we have developed an organ-on-chip coculture model derived from human induced pluripotent stem cells. The presence of pancreatic-derived tissue in the culture environment contributed to increase the CYP3A4 activity, the glycogen storage, and the expression of genes related to lipids, bile acids and sterol metabolism in the liver derived tissue. Concomitantly, the presence of liver cells led to increase the C-peptide secretion in pancreas. The coculture with liver modulated the pancreatic differentiation by increasing the activity of important transcription factors (REST, MAFB, PBX1) and by downregulating several hormone encoding genes (INS, GCG, TTR). The liver also stimulated the expression of genes involved in the response to inflammation in pancreas (via TGFβ/SMAD pathway). In parallel we observed a pancreatic cell reorganization coupled with the activation of the cell proliferation related transcription factor (SCRT1) and the upregulation of cellular remodeling genes (FLNA, FLNB, FN1, COL4A5). Finally, the pancreatic lipid genes were also upregulated in presence of the liver tissue. Overall, our results reflect a complex synergy between both tissues. We believe that those results are an encouraging step toward the development of relevant human model using advanced organ-on-chip technology and stem cells sources.

Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.

Metabolic dysfunction-associated steatotic liver disease (MASLD) featuring hepatic steatosis and insulin dysregulation is becoming a common cause of chronic hepatic diseases. Although the involvement of endocrine disruption in the onset and progression of MASLD is thought to be critical, there are limited effective animal models reflecting hyperinsulinemia and hepatic steatosis. Here, we propose a MASLD mouse model that combines neuropeptide effects and dietary nutrition. We employed chronic overexpression of the gene encoding neurosecretory protein GL (NPGL) in the hypothalamus of ICR mice under a low-fat/medium-sucrose diet (LFMSD). Npgl overexpression promoted fat accumulation in the white adipose tissues in 2 weeks. Basal insulin levels were increased and pancreatic islets expanded following Npgl overexpression. Histological and molecular biological approaches revealed that Npgl overexpression enhanced de novo lipogenesis, leading to hepatic steatosis. Nine-week overexpression of Npgl exacerbated obesity and hyperinsulinemia, resulting in hyperglycemia. Moreover, prolonged Npgl overexpression aggravated fat accumulation in the liver with a change in the lipid metabolic pathway. These findings suggest that Npgl overexpression readily leads to obesity with hyperinsulinemia and hepatic steatosis in ICR mice under an LFMSD.

The Atherogenic Index of Plasma (AIP), calculated by log (Triglycerides/HDL-C), has been proposed as a marker of atherogenic and cardiovascular risk. Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) share some pathogenic features and may be considered clinical manifestations of Metabolic Syndrome. In this study, we aimed to investigate the role of increased AIP as a putative metabolic biomarker for MASLD. 1,496 individuals (49% males and 51% females) underwent clinical examination for Metabolic Syndrome at Internal Medicine Division "C. Frugoni" of University Hospital of Bari, Italy in the period between January 2016 and April 2024. Clinical history was recorded, and physical examination, anthropometric measures, biochemical assessment, and abdomen ultrasound were performed. In the overall population, AIP significantly correlated with fasting glycemia (FPG, r = 0.26, p < 0.0001), HbA1c (r = 0.20, p < 0.0001), LDL (r = 0.11, p < 0.0001) and total cholesterol (r = 0.09; p < 0.0001), and anthropometric measures of obesity BMI (r = 0.37, p < 0.0001) and Waist Circumference (r = 0.44; p < 0.001). We then investigated AIP values in patients with and without dysmetabolic conditions, finding that AIP significantly increased as steatosis worsened (p < 0.001). ROC curves identified an optimal cut-off of 0.31 for accurately diagnosing severe steatosis and AIP values above this cut-off discriminated patients with significantly increased (p < 0.0001) fasting glycemia, LDL, and waist circumference, and were strongly associated (p < 0.0001) with MASLD (LLR 85.3), type 2 diabetes (LLR 85.5), abdominal obesity (LLR 72.9), overweight (LLR 151.8), and systemic obesity (LLR 178.4). The risk for being diagnosed with such conditions was found to be even higher in the subpopulation of patients with severe liver steatosis. To validate our findings, we considered another cohort of patients with and without biopsy-proven liver steatosis (public dataset GSE89632), confirming that a significant increase (p < 0.001) in AIP values could be found in patients with liver steatosis compared to healthy controls. AIP can be considered a specific biomarker of fatty liver disease with high sensitivity for the diagnosis of the severe form of liver steatosis. Considering AIP in the evaluation of patients with liver steatosis may augment the accuracy for diagnosing metabolic impairment and MASLD.

Features of the cardiometabolic syndrome are prevalent in patients with familial hypercholesterolemia (FH). Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, a surrogate marker of insulin resistance, may be a robust predictor of cardiac events in the general population. We explored the association between TG/HDL-C ratio and high-risk coronary artery plaque (HRP) and hepatic steatosis (HS) in asymptomatic patients with FH.

We conducted a cross-sectional study of 290 patients (mean age = 49 years, 44% male) who underwent computed tomography coronary angiography for cardiovascular risk assessment. HRP and HS were assessed from computed tomography coronary angiography, and TG/HDL-C ratio was derived from the fasting lipid panel collected around time of scanning. Associations were assessed using binary logistic and Kaplan-Meier analysis.

TG/HDL-C ratio was significantly associated with HRP (odds ratio, 1.27; 95% CI, 1.04-1.56; P = .020) and HS (odds ratio, 1.71; 95% CI, 1.17-2.51; P = .005) after adjusting for age, body mass index, smoking, and coronary calcium score. TG/HDL-C ratio was associated with HRP in patients treated with lipid-lowering medications (P = .042) and inclusion in a predictive model outperformed the FH-Risk-Score (area under receiver operating characteristic 0.74 vs 0.63; P = .004). An elevated TG/HDL-C ratio predicted myocardial infarction or coronary revascularization over a median follow-up of 91 months with 10 cardiac events recorded (P = .043). TG/HDL-C ratio was strongly positively correlated (P < .001 for all) with markers of cardiometabolic dysfunction: lipid accumulation product (r = 0.81), visceral adiposity index (r = 0.96), and triglyceride-glucose index (r = 0.91).

TG/HDL-C ratio was strongly associated with HRP, HS, and cardiac events in patients with FH treated with long-term cholesterol-lowering therapy.

Owing to long-term antiretroviral therapy (ART), the incidence of non-HIV-related chronic diseases is increasing, and liver disease is the leading cause of increased AIDS mortality. Moreover, the prevalence of NAFLD and liver fibrosis has been reported to vary widely across regions and studies. There is no precise description of the trend and characteristics of NAFLD in PLWH. Here, we aimed to explore the prevalence and outcomes of NAFLD in people living with HIV (PLWH).

The PubMed, Web of Science, Embase, and Cochrane Library databases were searched on August 15, 2023, for studies that evaluated the prevalence of NAFLD or liver fibrosis among PLWH. The meta-synthesized effects of NAFLD and liver fibrosis were the primary outcomes, and potential moderators were the secondary outcomes. The meta-analysis of the combined event rate (ER) and random effects was conducted on the basis of the number of individuals with NAFLD, the number of individuals with liver fibrosis, and the total sample size.

Of the 3520 studies identified, 41 studies were eligible for the meta-analysis. The results revealed that the combined ERs of NAFLD and liver fibrosis were 0.38 (95% CI: 0.33-0.43, p < 0.01) and 0.25 (95% CI: 0.18-0.32, p < 0.01), respectively.

This meta-analysis provided empirical evidence that the prevalence of NAFLD and liver fibrosis in PLWH is greater than that in the general population, which requires sufficient attention. In the HIV population, noninvasive imaging to monitor NAFLD changes should be strengthened, and a high TG level might be an early predictive indicator for HIV-associated fatty liver disease; however, large-scale prospective clinical research data are still needed for further validation and evaluation.

Background and Objectives: Type 2 diabetes (T2D), closely associated with obesity, contributes to increased morbidity and mortality due to complications such as cardiometabolic disease. This review aims to evaluate the effectiveness of metabolic and bariatric surgeries (MBS) and endoscopic bariatric therapies (EBTs) in achieving diabetes remission and to examine key predictors influencing remission outcomes. Materials and Methods: This review synthesizes data from studies on MBS and EBT outcomes, focusing on predictors for diabetes remission such as preoperative insulin use, diabetes duration, HbA1c, and C-peptide levels. Additionally, predictive scoring systems, including the Individualized Metabolic Surgery (IMS), DiaRem, Advanced-DiaRem, ABCD, and Robert et al. scores, were analyzed for their utility in forecasting remission likelihood. Results: Key predictors of T2D remission include shorter diabetes duration, lower HbA1c, and higher C-peptide levels, while prolonged insulin use, and higher insulin doses are associated with lower remission rates. Scoring models like IMS and DiaRem demonstrate that lower scores correlate with a higher likelihood of remission, especially for procedures such as Roux-En-Y gastric bypass (RYGB). RYGB generally shows higher remission rates compared to sleeve gastrectomy (SG), particularly among patients with mild disease severity, while EBTs like ESG and IGBs contribute 5-20% total weight loss (TWL) and moderate glycemic control improvements. Conclusions: Both MBS and EBTs are effective for T2D management, with predictive scoring models aiding in individualized patient selection to optimize remission outcomes. Further research to validate these predictive tools across diverse populations could enhance treatment planning for both surgical and endoscopic interventions.

Metabolic-associated fatty liver disease (MAFLD) and atherosclerosis are very common disorders that frequently coexist. The therapeutic efficacy of Huanglian Wendan (HLWD) decoction, a traditional Chinese medicine (TCM) prescription, is satisfactory in treating MAFLD associated with atherosclerosis. However, the underlying mechanisms through which HLWD exerts its effects need to be elucidated. Given the complex composition of HLWD and its multiple therapeutic targets, pharmacological investigation is challenging.

This study aimed to identify the effective compounds in HLWD and elucidate the mechanisms involved in its therapeutic effect on MAFLD associated with atherosclerosis.

We used a systematic pharmacology method to identify effective compounds present in HLWD and determine the mechanism by which it affects MAFLD associated with atherosclerosis. The effective components of HLWD were identified through ultrahigh-performance liquid chromatography-q exactive-orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). Next, a comprehensive in silico method was used to predict potential related targets and disease targets for these compounds to establish corresponding pathways. The accuracy of our assumed systemic pharmacology results was determined by conducting follow-up experiments.

By conducting UHPLC-Q-Orbitrap HRMS combined with network analysis, we identified 18 potentially active components of HLWD and assessed the inflammatory regulatory mechanism by which it affects MAFLD associated with atherosclerosis on the basis of 52 key targets. We used a high-fat, high-cholesterol (HFHC)-induced mice model of MAFLD associated with atherosclerosis to confirm our results. We found that administering HLWD significantly improved the appearance of their liver and reduced their body weight, liver weight, blood lipids, hepatic damage, and hepatic pathology. HLWD also decreased atherosclerotic lesion areas, foam cells, and inflammatory cells in the aorta. HLWD showed anti-inflammatory effects, suppressed M1 polarization, and promoted M2 polarization in the liver and aorta. HLWD might also regulate peroxisome proliferator-activated receptor-γ (PPARγ)/nuclear factor kappa-B (NF-κB) signaling to influence macrophage polarization and inflammation.

Our results showed that HLWD protected against HFHC diet-induced MAFLD associated with atherosclerosis by regulating PPARγ/NF-κB signaling, thus adjusting macrophage polarization and inflammation. Additionally, pharmacochemistry research, network pharmacology analysis, and experimental verification can be combined to form a comprehensive model used in studies on TCM.

Insulin resistance describes the lack of activity of a known quantity of insulin (exogenous or endogenous) to promote the uptake of glucose and its utilization in an individual, as much as it does in metabolically normal individuals. On the cellular level, it suggests insufficient power of the insulin pathway (from the insulin receptor downstream to its final substrates) that is essential for multiple mitogenic and metabolic aspects of cellular homeostasis. Atherosclerosis is a slow, complex, and multifactorial pathobiological process in medium to large arteries and involves several tissues and cell types (immune, vascular, and metabolic cells). Inflammatory responses and immunoregulation are key players in its development and progression. This paper examines the possible pathophysiological mechanisms that govern the connection of insulin resistance, hyperinsulinemia, and the closely associated cardiometabolic syndrome with atherosclerosis, after exploring thoroughly both in vitro and in vivo (preclinical and clinical) evidence. It also discusses the importance of visualizing and developing novel therapeutic strategies and targets for treatment, to face this metabolic state through its genesis.

The excessive accumulation of intrahepatic triglyceride (IHTG) in the liver is a risk factor for metabolic diseases, including type 2 diabetes and cardiovascular disease. IHTG can excessively accumulate owing to imbalances in the delivery, synthesis, storage and disposal of fat to, in and from the liver. Although obesity is strongly associated with IHTG accumulation, emerging evidence suggests that the composition of dietary fat, in addition to its quantity, plays a role in mediating IHTG accumulation. Evidence from human cross-sectional and interventional studies indicates that diets enriched with saturated fat compared to other fat types and carbohydrates produce divergent effects on IHTG content. However, the mechanistic reasons for these observations remain unknown. Given the challenges of investigating such mechanisms in humans, cellular models are needed that can recapitulate human hepatocyte fatty acid metabolism. Here, we review what is known from human studies about how dietary fat, its quantity and composition contribute to IHTG accumulation. We also explore the effects of fatty acid composition on hepatocellular fat metabolism from data generated in cellular models to help explain the divergences observed in in vivo studies.

Non-alcoholic fatty liver disease (NAFLD) is a liver pathology concomitant with metabolic disarrangement. This study assessed the therapeutic impacts of delphinidin, an anthocyanin, or α-amyrin, a pentacyclic triterpenoid, on NAFLD in rats and the underlying mechanisms involved. NAFLD was established by feeding a high-fat diet (HFD) for 10 weeks, either alone or in combination with delphinidin (40 mg/kg, oral) or α-amyrin (20 mg/kg, oral). Delphinidin or α-amyrin ameliorated the metabolic and histopathological perturbations induced by HFD. These compounds markedly attenuated NAFLD-induced hepatic steatosis, as evidenced by a substantial decrease in body weight, insulin resistance, and liver and adipose tissue indices. Alongside normalization of the atherogenic index, both improved HFD-mediated abnormalities in serum lipids, liver enzymes, leptin, and ghrelin levels. Moreover, their intervention activated the NFE2 like bZIP transcription factor 2 and heme oxygenase 1 pathways and abrogated HFD-triggered activation of mitogen-activated protein kinase 1 signaling. These remedies inhibited hepatic apoptosis and modulated the gene expression of lipogenic enzymes. Furthermore, histological analysis corroborated the suppression of lipid accumulation and amelioration of hepatic architecture in the treated rats. Our findings highlight the hepatoprotective value of delphinidin or α-amyrin against NAFLD and related metabolic diseases through their insulin-sensitizing, anti-inflammatory, antioxidant, and antiapoptotic effects.

Hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia are interconnected metabolic disorders. This study is designed to characterize how microRNA-206-3p (miR-206) simultaneously prevents de novo lipogenesis (DNL), cholesterol synthesis, and VLDL production in hepatocytes while promoting cholesterol efflux in macrophages.

MiR-206 levels were reduced in hepatocytes and macrophages of mice subjected to a high-fat, high-cholesterol diet. A negative feedback between LXRα (liver X receptor alpha) and miR-206 is formed to maintain high LXRα and low miR-206 in hepatocytes. Systemic administration of miR-206 alleviated hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia in mice. A significant reduction in LDL cholesterol and VLDL cholesterol but unaltered HDL cholesterol was observed in miR-206-treated mice. Mirroring these findings, miR-206 reprogrammed the transcriptome of hepatocytes towards the inhibition of DNL, cholesterol synthesis, and assembly and secretion of VLDL. In macrophages, miR-206 activated the expression of genes regulating cholesterol efflux. Hepatocyte-specific expression of miR-206 reduced hepatic and circulating triglycerides and cholesterol, as well as VLDL production, while transplantation of macrophages bearing miR-206 facilitated cholesterol efflux. Mechanistically, miR-206 directly targeted Lxrα and Hmgcr in hepatocytes but facilitated expression of Lxrα in macrophages by targeting macrophage-specific tricho-rhino-phalangeal syndrome 1 (TRPS1), a transcription repressor of Lxrα . By targeting Hmgc r and Lxrα , miR-206 inhibited DNL, VLDL production, and cholesterol synthesis in hepatocytes, whereas it drove cholesterol efflux by activating the TRPS1-LXRα axis.

MiR-206, through differentially modulating LXRα signaling in hepatocytes and macrophages, inhibits DNL, promotes cholesterol efflux, and concurrently hinders cholesterol synthesis and VLDL production. MiR-206 simulates the functions of lipid-lowering medications, statins, and LXRα agonists.

Dyslipidemias are major risk factors for cardiovascular disease, and other comorbidities. The focus on food and nutrition to prevent and treat cardiovascular risk factors including dyslipidemia is a paradigm shift. This is the first meta-analysis to assess the association of dates fruit and dyslipidemia in Type-2 diabetes. The study aimed to assess the same among patients with Type-2 diabetes.

Six databases were searched for relevant articles from inception to March 2024. We included randomized trials, studies with other methods, and those conducted among healthy people were excluded. A structured checklist including the author's name, country, year of publication, study type, duration of the study, lipid profile at baseline and after-dates fruit consumption, age, and gender of participants, type of dates, and the amount consumed.

Out of the 448 studies retrieved, fourteen cohorts from four studies (298 participants with Type-2 diabetes) were included. Dates fruit reduced cholesterol, odd ratio, -0.87, 95% CI, -1.39--0.35, P-value, 0.001, and I2 for heterogeneity=90%. No significant changes were observed on low-density lipoprotein (odd ratio, -0.31, 95% CI, -0.65-0.03, and P-value, 0.08), triglycerides (odd ratio, -0.77, 95% CI, -2.17--0.63, P-value 0.28), and high-density lipoproteins (odd ratio, 0.03, 95% CI, -0.13-0.19, P-value, 0.69). The I2 for heterogeneity were=99%, 95%, and 65% respectively.

Dates fruit could reduce total cholesterol, with a non-significant reduction in low-density lipoproteins. No significant effect was evident regarding triglycerides and high-density lipoproteins. Further larger studies with a high selection of controls and dates are needed.

Functional probiotics, particularly Lactobacillus delbrueckii subsp. lactis CKDB001, have shown potential as a therapeutic option for metabolic dysfunction-associated steatotic liver disease (MASLD). However, their effects have not been confirmed in in vivo systems. Here, we investigated the effects of L. delbrueckii subsp. lactis CKDB001 on insulin resistance, dyslipidemia, MASLD, and lipid metabolism in a murine model of high-fat diet (HFD)-induced obesity.

The mice were divided into four groups (n = 12 per group)-normal chow diet (NCD), high fat diet (HFD), HFD with L. delbrueckii subsp. lactis CKDB001 (LL), and HFD with resmetirom (positive control (PC), a thyroid receptor β agonist). The experimental animals were fed NCD or HFD for 12 weeks, followed by an additional 12-week oral treatment with LL or resmetirom.

LL supplementation reduced body weight, insulin levels, and HOMA-IR compared with those in the HFD group, indicating improved insulin sensitivity. Additionally, LL reduced serum triglyceride (TG) levels without affecting total cholesterol (TC) levels. HFD consumption increased liver weight and hepatic TG and TC levels, indicating ectopic fat accumulation; however, LL supplementation reversed these changes, indicating a liver-specific effect on cholesterol metabolism. Furthermore, LL administration attenuated NAFLD activity scores, reduced hepatic fibrosis, improved liver function markers (aspartate aminotransferase), and enhanced Adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. However, LL did not considerably affect the expression of genes related to lipid metabolism. In epididymal adipose tissue, LL treatment reduced leptin levels but had no effect on adiponectin; additionally, histological analysis showed an increase in adipocyte size, potentially linked to enhanced energy metabolism.

Collectively, these findings suggest that LL could be a promising therapeutic candidate for improving insulin sensitivity, reducing hepatic lipid accumulation, and mitigating MASLD.

Objective While studies have documented how metabolic dysfunction-associated steatotic liver disease (MASLD) can contribute to cardiovascular disease (CVD), whether MASLD is associated with myocardial infarction (MI) remains debateable. Herein, we systematically reviewed published articles and performed a meta-analysis to determine the relationship between MASLD and MI risk.Methods PubMed, MEDLINE, Embase, Web of Science, CNKI, CBM, VIP, and WanFang databases were searched, and the DerSimonian Laird method was used to obtain hazard ratios (HRs) for binary variables to assess the correlation between MASLD and MI risk. Subgroup analyses for the study region, MASLD diagnosis, quality score, study design, and follow-up time were conducted simultaneously for the selected studies retrieved from the time of database establishment to March 2022. All study procedures were independently conducted by two investigators.Results The final analysis included seven articles, including eight prospective and two retrospective cohort studies. The MI risk was higher among MASLD patients than among non-MASLD patients (HR = 1.26; 95% CI: 1.08-1.47, p = 0.003). The results of the subgroup analysis of the study region revealed an association of MASLD with MI risk among Americans and Asians, but not in Europeans. Subgroup analyses of MASLD diagnosis showed that ultrasonography and other (fatty liver index[FLI] and computed tomography [CT)]) diagnostic methods, but not international classification of disease (ICD), increased the risk of MI. Subgroup analysis of the study design demonstrated a stronger relationship between MASLD and MI in retrospective studies but not in prospective studies. Subgroup analysis based on the follow-up duration revealed the association of MASLD with MI risk in cases with < 3 years of follow-up but not with ≥3 years of follow-up.Conclusion MASLD increases the risk of MI, independent of traditional risk factors.

There is currently limited evidence comparing the association between metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic fatty liver disease (NAFLD), and the risk of peripheral artery disease (PAD). This study aims to analyze the associations of MAFLD and NAFLD with incident PAD.

Two longitudinal studies, the UKB (UK Biobank) study (n=372 216) and the ARIC (Atherosclerosis Risk in Communities) study (n=4681), categorized participants into MAFLD/non-MAFLD groups and NAFLD/non-NAFLD groups. Subsequently, participants were classified into 4 groups: non-fatty liver disease, MAFLD-only, NAFLD-only, and both MAFLD and NAFLD groups. Cox proportional hazard model estimated associations of MAFLD/NAFLD status, subtypes, and liver fibrosis severity with PAD risk. The MAFLD group had a higher risk of incident PAD compared with the non-MAFLD group, and similarly, the NAFLD group had a higher risk compared with the non-NAFLD group. Among these 4 groups, the MAFLD-only group had the strongest association with the risk of incident PAD, while the NAFLD-only group was not independently associated. Diabetic MAFLD subtype was significantly associated with increased PAD risk, and higher level of liver fibrosis scores correlated with elevated PAD risk.

Both MAFLD and NAFLD are significantly associated with an increased incidence of PAD, with stronger associations in MAFLD and diabetic MAFLD population. These findings emphasize that the need for screening and prevention strategies for PAD in this high-risk population is warranted. The assessment of MAFLD and its subtypes should be considered as an integral component of cardiovascular risk assessment.

Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity globally, and with the prevalence of metabolic-related diseases, the incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) related hepatocellular carcinoma (MAFLD-HCC) continues to rise with the limited efficacy of conventional treatments, which has created a major challenge for HCC surveillance. Immune checkpoint inhibitors (ICIs) and molecularly targeted drugs offer new hope for advanced MAFLD-HCC, but the evidence for the use of both types of therapy in this type of tumour is still insufficient. Theoretically, the combination of immunotherapy, which awakens the body's anti-tumour immunity, and targeted therapies, which directly block key molecular events driving malignant progression in HCC, is expected to produce synergistic effects. In this review, we will discuss the progress of immunotherapy and molecular targeted therapy in MAFLD-HCC and look forward to the opportunities and challenges of the combination therapy.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern closely linked to metabolic disorders, including obesity, insulin resistance, and dyslipidemia. Emerging evidence suggests that the gut-liver axis plays a critical role in the pathogenesis of NAFLD, with recent research highlighting the influence of gut microbiota, including fungal species such as Saccharomyces boulardii (S. boulardii). This study aimed to evaluate the effects of S. boulardii on lipid metabolism and oxidative stress in a rat model of fructose-induced NAFLD. Materials and Methods: Thirty Wistar rats were divided into three groups: a control group, a fatty liver group induced by 35% fructose supplementation, and a treatment group receiving S. boulardii (100 mg/kg/day) after fructose induction. Results: Biochemical analyses revealed that the treatment group exhibited significantly lower plasma levels of malondialdehyde (MDA), alanine aminotransferase (ALT), total triglycerides, and cholesterol compared to the untreated fatty liver group (p < 0.05). Furthermore, liver tissue analysis showed a marked reduction in lipid accumulation and fatty infiltration in the treatment group, with no visible lipid vacuoles in hepatocytes. The expression of aquaporin-8 (AQP8) and sirtuin-1 (SIRT1), key markers associated with hepatocyte function and lipid metabolism, was significantly higher in the S. boulardii group compared to the fatty liver group (p < 0.001). Conclusions: These findings indicate that S. boulardii supplementation mitigates the metabolic and oxidative stress-related alterations associated with fructose-induced NAFLD. In conclusion, our study suggests that S. boulardii exerts protective effects on the liver by reducing lipid accumulation and oxidative stress, highlighting its potential as a therapeutic intervention for NAFLD.

The metabolic syndrome (MetS) is a multiplex modifiable risk factor for cardiovascular disease, type 2 diabetes mellitus and other health outcomes, and is a major challenge to clinical practice and public health. The rising global prevalence of MetS, driven by urbanization, sedentary lifestyles and dietary changes, underlines the urgency of addressing this syndrome. We explore the complex underlying mechanisms, including genetic predisposition, insulin resistance, accumulation of dysfunctional adipose tissue and ectopic lipids in abdominal obesity, systemic inflammation and dyslipidaemia, and how they contribute to the clinical manifestations of MetS. Diagnostic approaches vary but commonly focus on abdominal obesity (assessed using waist circumference), hyperglycaemia, dyslipidaemia and hypertension, highlighting the need for population-specific and phenotype-specific diagnostic strategies. Management of MetS prioritizes lifestyle modifications, such as healthy dietary patterns, physical activity and management of excess visceral and ectopic adiposity, as foundational interventions. We also discuss emerging therapies, including new pharmacological treatments and surgical options, providing a forward-looking perspective on MetS research and care. This Primer aims to inform clinicians, researchers and policymakers about MetS complexities, advocating for a cohesive, patient-centred management and prevention strategy. Emphasizing the multifactorial nature of MetS, this Primer calls for integrated public health efforts, personalized care and innovative research to address this escalating health issue.

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease. Studies have found that ezetimibe may be utilized as a supplemental treatment for NAFLD. Additionally, many clinical trials reported the potential impacts of ezetimibe on patients with NAFLD, although some conclusions remain controversial. Therefore, this study aimed to evaluate the effects of ezetimibe on patients with NAFLD.

Online search was conducted across databases including PubMed, Embase, Scopus, Web of Science, Cochrane Library, Wanfang, VIP, and CNKI to retrieve all relevant controlled studies on the treatment of NAFLD with ezetimibe from the inception of the databases until April 2024. This meta-analysis comprised 10 randomized controlled trials (RCTs). Statistical analysis was conducted using the Meta package in R v4.3.2.

A total of ten RCTs were included in this study, encompassing 578 patients (290 in the ezetimibe group and 288 in the control group) diagnosed with NAFLD/non-alcoholic steatohepatitis (NASH). The results indicated that ezetimibe significantly reduced levels of aspartate aminotransferase (P < 0.01), glutamyl transferase (γ-GT) (P < 0.01), total cholesterol (P < 0.01), low-density lipoprotein cholesterol (P < 0.01), high-sensitivity C-reactive protein (P < 0.01), and interleukin-6 (P < 0.01), and markedly increased levels of glycated hemoglobin (P = 0.02).

Ezetimibe may partially improve transaminase levels and positively impact liver function in patients with NAFLD/NASH.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023461467.

Peripheral arterial calcification is a prevalent condition in patients with type 2 diabetes mellitus (T2DM), resulting in lower-limb amputation and reduced life quality. Non-alcoholic fatty liver disease (NAFLD), which can be simply evaluated using the fatty liver index (FLI), is closely associated with T2DM development. In this study, we aimed to explore the relationship between FLI and lower limb arterial calcification (LLAC) in T2DM patients and to reveal the value of T2DM patients with NAFLD in predicting the occurrence of LLAC.

A total of 77 T2DM patients with LLAC who underwent comprehensive physical and health examinations, serological examinations, as well as lower limb computed tomography imaging at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between January 2018 and January 2019 were enrolled in this study. The FLI was calculated using body mass index, waist circumference, triglycerides, and γ-glutamyl transferase. Additionally, LLAC was evaluated using computed tomography with the Agatston scoring algorithm. The patients were divided into three groups based on their FLI values: Non-liver disease group (FLI <30, n = 29), borderline-liver disease group (30 ≤ FLI < 60, n = 32), and NAFLD group (FLI ≥60, n = 16). Univariate and multivariate binary logistic regression analyses were employed to investigate the association between FLI and LLAC in T2DM patients. Furthermore, differences in LLAC among groups were analyzed using post-hoc multiple comparisons and ordinal logistic regression model analysis.

Univariate and multivariate analyses showed that age and FLI influenced LLAC severity in T2DM patients. Moreover, T2DM patients in the NAFLD group had significantly lower LLAC scores than those in the Non-liver disease group. The correlation analysis showed that FLI was negatively associated with LLAC scores (R = -0.31, p = 0.006), while age was positively associated (R = 0.361, p = 0.001).

Our study revealed an inverse relationship between FLI and the degree of LLAC. This indicates that, based on evidence in the current research, NAFLD may not be reliable as a predictor of LLAC in T2DM patients.

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 steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease (NAFLD), and gastroesophageal reflux disease (GERD) are prevalent chronic conditions with escalating global incidence. This study delves into the intricate interplay between MASLD and GERD. The primary objective is to comprehensively explore the association between MASLD and GERD, investigating how various factors contribute to the coexistence and potential exacerbation of these conditions. We conducted a literature search in PubMed and Google Scholar of only human studies over the past 10 years. The search included systematic review, meta-analysis, editorial, and cross-sectional studies of patients with MASLD and GERD. The prevalence of GERD in patients with MASLD was higher, with various risk factors coming into play. Obesity was identified as an independent risk factor for both GERD and MASLD. However, obese patients predominantly had higher disease progression. Lifestyle factors like physical activity and dietary modifications emerge as promising strategies to mitigate risk.

The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population.

Ninety-eight young, healthy, underweight women participated in this study.

To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively.

Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR.

Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels.

Metabolic dysfunction associated steatotic liver disease (MASLD) contributes to the cardiometabolic diseases through multiple mechanisms. Fatty liver index (FLI) has been formulated as a non-invasive, convenient, and cost-effective approach to estimate the degree of MASLD. The current study aims to evaluate the correlation between FLI and the prevalent cardiometabolic multimorbidity (CMM), and to assess the usefulness of FLI to improve the detection of the prevalent CMM in the general population.

26,269 subjects were enrolled from the National Health and Nutrition Examination Survey 1999-2018. FLI was formulated based on triglycerides, body mass index, γ -glutamyltransferase, and waist circumference. CMM was defined as a history of 2 or more of diabetes mellitus, stroke, myocardial infarction.

The prevalence of CMM was 10.84%. With adjustment of demographic, anthropometric, laboratory, and medical history covariates, each standard deviation of FLI leaded to a 58.8% risk increase for the prevalent CMM. The fourth quartile of FLI had a 2.424 times risk for the prevalent CMM than the first quartile, and a trend towards higher risk was observed. Smooth curve fitting showed that the risk for prevalent CMM increased proportionally along with the elevation of FLI. Subgroup analysis demonstrated that the correlation was robust in several conventional subpopulations. Receiver-operating characteristic curve analysis revealed an incremental value of FLI for detecting prevalent CMM when adding it to conventional cardiometabolic risk factors (Area under the curve: 0.920 vs. 0.983, P < 0.001). Results from reclassification analysis confirmed the improvement from FLI.

Our study demonstrated a positive, linear, and robust correlation between FLI and the prevalent CMM, and our findings implicate the potential usefulness of FLI to improve the detection of prevalent CMM in the general population.

Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease.

We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF.

TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF.

In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.

There is a significant association of non-alcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD). Most CVDs begin with atherosclerosis in the arteries, which can be reliably measured as the carotid intima-media thickness (CIMT) by ultrasound. Given that ethnic and regional differences have an impact on NAFLD, we aimed to evaluate the association of NAFLD patients from India with subclinical atherosclerosis, measured as CIMT. A thorough literature search was performed on four electronic databases using combinations of several keywords. The relevant data were pooled in a random or fixed-effect model, based on heterogeneity, to calculate the pooled standardised mean difference (SMD), or odds ratio (OR) with 95% confidence interval (CI). The final analysis included a total of 15 studies with 1196 NAFLD and 1482 control subjects. NAFLD patients had a 21.3% higher mean CIMT than the controls. The pooled SMD was 1.001 (95% CI: 0.627-1.375, p < 0.001). Three studies that balanced cardiometabolic risk factors found a similar association (p = 0.037). Furthermore, NAFLD was significantly associated with the presence of high (>0.8 mm) CIMT (pooled OR = 5.4, 95% CI: 2.0-14 .9) and carotid plaques (pooled OR = 10.24, 95% CI: 5.74-18.26). The mean CIMT was also higher in diabetic NAFLD than in the diabetic control (pooled SMD = 1.07, 95% CI = 0.818-1.324, p < 0.001). There is a significant positive association between the marker of subclinical atherosclerosis and NAFLD in India. This might give more light on screening and follow-up plans for such patients.

Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with an increased risk of coronary artery disease. Computed Tomography Coronary Angiography (CTCA) can assess both the extent and the features of coronary plaques. We aimed to gather evidence about the prevalence and features of coronary plaques among MASLD patients.

PubMed, Scopus, and Google Scholar databases were searched for randomized controlled trials and adjusted observational studies assessing the prevalence and features of coronary plaques by means of CTCA in MASLD patients as compared with a control group. The prevalence of coronary stenosis (defined as >30% and >50% diameter of stenosis), of increasing coronary artery calcium (CAC) score and of high-risk features (namely low-attenuation plaques, napkin ring sign, spotty calcification and positive remodelling) in MASLD patients were the endpoints of interest.

Twenty-four observational studies were included. MASLD was associated with an increased prevalence of critical coronary stenosis compared with controls (odds ratio [OR] 1.54, 95%CI 1.23-1.93). Increased values of CAC score were observed in MASLD patients (OR 1.35, 95%CI 1.02-1.78 and OR 2.26, 95%CI 1.57-3.23 for CAC score 0-100 and >100, respectively). An increased risk of 'high-risk' coronary plaques was observed in MASLD patients (OR 2.13, 95%CI 1.42-3.19). As high-risk features plaques, a higher prevalence of positive remodelling and spotty calcification characterize MASLD patients (OR 2.92, 95%CI 1.79-4.77 and OR 2.96, 95%CI 1.22-7.20).

Patients with MASLD are at increased risk of developing critical coronary stenosis and coronary plaques characterized by high-risk features as detected by CTCA.

Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERβ) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1β, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in the United States, encompassing a wide spectrum of liver pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite its high prevalence, there are no medications currently approved by the Food and Drug Administration for the treatment of NAFLD. Recent work has suggested that NAFLD has a strong genetic component and identifying causative genes will improve our understanding of the molecular mechanisms contributing to NAFLD and yield targets for future therapeutic investigations. Oxidative stress is known to play an important role in NAFLD pathogenesis, yet the underlying mechanisms accounting for disturbances in redox status are not entirely understood. To better understand the relationship between the glutathione redox system and signs of NAFLD in a genetically-diverse population, we measured liver weight, serum biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and graded liver pathology in a large cohort of Diversity Outbred mice. We compared hepatic endpoints to those of the glutathione redox system previously measured in the livers and kidneys of the same mice, and we screened for statistical and genetic associations using the R/qtl2 software. We discovered several novel genetic loci associated with markers of liver health, including loci that were associated with both liver steatosis and glutathione redox status. Candidate genes within each locus point to possible new mechanisms underlying the complex relationship between NAFLD and the glutathione redox system, which could have translational implications for future studies targeting NAFLD pathology.

The alarming increase in global rates of metabolic diseases (MetDs) and their association with cancer risk renders them a considerable burden on our society. The interplay of environmental and genetic factors in causing MetDs may be reflected in DNA methylation patterns, particularly at non-canonical (non-B) DNA structures, such as G-quadruplexes (G4s) or R-loops. To gain insight into the mechanisms of MetD progression, we focused on DNA methylation and functional analyses on intragenic regions of two MetD risk genes, the glucokinase (GCK) exon 7 and the transmembrane 6 superfamily 2 (TM6SF2) intron 2-exon 3 boundary, which harbor non-B DNA motifs for G4s and R-loops.Pyrosequencing of 148 blood samples from a nested cohort study revealed significant differential methylation in GCK and TM6SF2 in MetD patients versus healthy controls. Furthermore, these regions harbor hypervariable and differentially methylated CpGs also in hepatocellular carcinoma versus normal tissue samples from The Cancer Genome Atlas (TCGA). Permanganate/S1 nuclease footprinting with direct adapter ligation (PDAL-Seq), native polyacrylamide DNA gel electrophoresis and circular dichroism (CD) spectroscopy revealed the formation of G4 structures in these regions and demonstrated that their topology and stability is affected by DNA methylation. Detailed analyses including histone marks, chromatin conformation capture data, and luciferase reporter assays, highlighted the cell-type specific regulatory function of the target regions. Based on our analyses, we hypothesize that changes in DNA methylation lead to topological changes, especially in GCK exon 7, and cause the activation of alternative regulatory elements or potentially play a role in alternative splicing.Our analyses provide a new view on the mechanisms underlying the progression of MetDs and their link to hepatocellular carcinomas, unveiling non-B DNA structures as important key players already in early disease stages.

ZJU index, a novel calculation combining blood glucose, body mass index (BMI), lipids and liver functions, is closely related with non-alcoholic fatty liver disease (NAFLD). However, the correlation between ZJU index and hepatic steatosis and liver fibrosis has not been reported in the studies. This study aims to examine the correlation between these variables.

Data from the 2017-2020 NHANES were collected for a cross-sectional study, to explore the linear relationship between ZJU, liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) with multivariate linear regression models. Restricted cubic spline (RCS) regression and threshold effect analyses were utilized to describe the nonlinear relationship. The correlation in subgroups was analyzed based on race, gender, drinking, age, BMI, diabetes and moderate activities.

In this population-based study, a total of 2,122 adults aged 18-80 years old with NAFLD were included. According to the multivariate linear regression analysis, ZJU had a significant positive correlation with liver fibrosis (LSM, β = 0.182, 95%CI = 0.154-0.211, p < 0.001) and hepatic steatosis (CAP, β = 2.35, 95%CI = 2.14-2.56, p < 0.001), which was stronger in males. According to the RCS analysis, an inverted L-shaped relationship between ZJU and CAP (inflection point at 60.56) and a J-shaped relationship between ZJU index and LSM (inflection point at 51.27) were observed.

ZJU had a positive correlation with CAP and LSM in American adults with NAFLD. The findings suggest that ZJU may be a valuable biomarker for assessing the severity of liver fibrosis and hepatic steatosis in individuals with NAFLD.

We aimed to investigate the correlation and to explore which MAFLD subtypes have the greatest influence on progression of arterial stiffness risk.

Using data from a health examination-based cohort, a total of 12,129 participants who underwent two repeated health examinations that included brachial-ankle pulse wave velocity (baPWV) from 2012 to 2020 were enrolled. Participants were separated into non-MAFLD, overweight/obese (OW-MAFLD), lean/normal weight (lean-MAFLD) and diabetes (DM-MAFLD) groups. Among the participants with a median follow-up of 2.17 years, 4511 (37.2%) participants had MAFLD at baseline, among which 3954 (87.7%), 123 (2.7%), and 434 (9.6%) were OW-, lean- and DM-MAFLD, respectively. Analyses using linear regression models confirmed that compared with the non-MAFLD group, the elevated baPWV change rates (cm/s/year) were 12.87 (8.81-16.94), 25.33 (7.84-42.83) and 38.49 (27.88-49.10) in OW, lean and DM-MAFLD, respectively, while the increased change proportions (%) were 1.53 (1.10-1.95), 3.56 (1.72-5.40) and 3.94 (2.82-5.05), respectively. Similar patterns were observed when these two baPWV parameters were transformed in the form of the greatest increase using Cox proportional hazards model analyses. Furthermore, the risk of arterial stiffness progression across MAFLD subtypes presented a significant, gradient, inverse relationship in the order of DM-, lean-, OW with metabolic abnormalities (MA)-, and OW without MA-MAFLD.

MAFLD, especially DM-MAFLD and lean-MAFLD, was significantly associated with arterial stiffness progression, providing evidence that stratification screening and surveillance strategies for CVD risk have important clinical implications.

More effective treatments for hepatitis viral infections have led to a reduction in the incidence of liver cirrhosis. A high-fat diet can lead to chronic hepatitis and liver fibrosis, but the effects of lipid intake on liver disease status, including hepatitis C virus and alcohol, after elimination of the cause are unclear. To investigate the effects, we used a rat cirrhosis model and a high-fat diet in this study. Male Wistar rats were administered carbon tetrachloride for 5 weeks. At 12 weeks of age, one group was sacrificed. The remaining rats were divided into four groups according to whether or not they were administered carbon tetrachloride for 5 weeks, and whether they were fed a high-fat diet or control diet. At 12 weeks of age, liver fibrosis became apparent and then improved in the groups where carbon tetrachloride was discontinued, while it worsened in the groups where carbon tetrachloride was continued. Liver fibrosis was notable in both the carbon tetrachloride discontinuation and continuation groups due to the administration of a high-fat diet. In addition, liver precancerous lesions were observed in all groups, and tumor size and multiplicity were higher in the high-fat diet-fed groups. The expression of genes related to inflammation and lipogenesis were upregulated in rats fed a high-fat diet compared to their controls. The results suggest that a high-fat diet worsens liver fibrosis and promotes liver carcinogenesis, presumably through enhanced inflammation and lipogenesis, even after eliminating the underlying cause of liver cirrhosis.

This study explored the potential of saponins from Korean Red Ginseng to target the PINK1/Parkin mitophagy pathway, aiming to enhance insulin sensitivity in hepatocytes-a key factor in metabolic disorders like metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. Results from both in vitro and in vivo experiments showed increased expression of PINK1 and Parkin, activating mitophagy and reducing oxidative stress through reduction in mitochondrial and total reactive oxygen species. Additionally, improvements in insulin signaling were observed, including the upregulation of phosphorylated IRS and AKT, and downregulation of gluconeogenic enzymes, underscoring the saponins' efficacy in boosting insulin sensitivity. The findings highlighted Korean Red Ginseng-derived saponins as potential treatments for insulin resistance and related metabolic conditions.

The escalating incidence of nonalcoholic fatty liver disease (NAFLD) is closely associated with a high-fat diet, leading to a decline in quality of life and significant health impairment. 7-Hydroxyflavone (7-HY) is a flavonoid known for its anti-inflammatory, anticarcinogenic, and antioxidant effects. This study aims to assess the ameliorative effects of 7-HY on NAFLD induced by a high-fat diet and elucidate underlying mechanisms. Oleic acid/palmitic acid-induced HepG2 cells and C57BL/6 mice on a high-fat diet were utilized as in vitro and in vivo models. In animal experiments, 7-HY was utilized as a dietary supplement. The 15-week in vivo experiment monitored body weight, body fat percentage, glucose tolerance, insulin tolerance, and metabolic indexes. Commercial kits assessed triglyceride (TG) and total cholesterol levels in cells, liver tissue, and blood. Discovery Studio identified potential targets of 7-HY, compared with NAFLD-associated targets in the GeneCards database. Results indicated 7-HY mitigated fat accumulation, hepatic steatosis, and oxidative stress induced by a high-fat diet. Furthermore, 7-HY showed potential efficacy in ameliorating abnormal glucose metabolism and promoting energy metabolism. Reverse target finding and molecular docking demonstrated a robust interaction between 7-HY and serine/threonine kinase 24 (STK24). Subsequent experimental results confirmed 7-HY's ability to inhibit TG deposition in HepG2 cells through interaction with STK24. In conclusion, 7-HY demonstrated the capacity to alleviate high-fat diet-induced NAFLD, presenting a novel strategy for the prevention and treatment of NAFLD.

This study review aimed to consolidate current knowledge on the electrocardiographic abnormalities observed in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD).

This was a systematic review of studies on the association between MASLD and electrocardiographic abnormalities, published between January 1, 1946, and October 31, 2023. Data from eligible studies were extracted, analyzed, synthesized, and summarized.

We evaluated a total of 27 studies with 8,607,500 participants overall and 1,005,101 participants with MASLD. There was a statistically significant association between MASLD and prevalent atrial fibrillation (pooled OR: 1.34 95 % CI: 1.20-1.49, p < 0.001, n = 12), shorter QRS duration (pooled SMD: -0.073, 95 % CI: -0.144 - -0.001, n = 2, p = 0.048, n = 2), QTc prolongation (p < 0.001, n = 2), LVH (pooled OR: 1.48, 95 % CI: 1.25-1.75, p < 0.001, n = 3), low voltage (p < 0.001, n = 1), ST changes (OR: 1.41, 95 % CI: 1.04-1.91, p = 0.027, n = 1), T wave inversion (p < 0.001, n = 1), axis deviation (OR: 3.21, 95 % CI: 1.99-5.17, p < 0.001, n = 1), conduction defect (OR: 2.79, 95 % CI: 1.83-4.26, p < 0.001, n = 1) and bundle branch block (OR: 2.90, 95 % CI: 1.82-4.61, p < 0.001, n = 1), any persistent heart block (p < 0.001, n = 1), fragmented QRS (p < 0.001, n = 1), and p wave dispersion (p < 0.001, n = 1) CONCLUSION: MASLD is associated with multiple ECG abnormalities which are potential markers of early cardiac involvement, highlighting the multisystemic nature of MASLD. These specific ECG abnormalities could be used in screening and management algorithms to improve cardiac risk stratification in MASLD patients.

CRD42023477501.