Search Results (3,433)

Background/Objectives: As obesity continues to increase globally, it has become a major contributor to the growing burden of metabolic diseases, including type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD). Hepatic lipid accumulation during obesity contributes to oxidative stress and alterations in mitochondrial homeostasis, key features of NAFLD progression. This study investigated whether vitamin D insufficiency aggravates obesity-related hepatic steatosis in association with changes in hepatic sirtuin 1 (SIRT1) activity and nuclear factor erythroid 2–related factor 2 (Nrf2)-related antioxidant gene expression. Methods: Male C57BL/6J mice were maintained on one of three dietary regimens for 16 weeks: a normal diet (NOR; 10% fat containing 1000 IU vitamin D/kg), a high-fat diet (HF; 60% fat containing 1000 IU vitamin D/kg), or a vitamin D-deficient high-fat diet (HF + NVD; 60% fat with no added vitamin D). Results: Vitamin D insufficiency in HF-fed mice (HF + NVD) was associated with significantly higher hepatic triglyceride accumulation and lipid peroxidation than those observed in the HF group. A concomitant reduction in the expression of Nrf2-dependent antioxidant genes was observed in the HF + NVD group. Furthermore, hepatic mitochondrial DNA content as well as hepatic SIRT1 mRNA level and activity, the NAD⁺/NADH ratio, and CPT1α mRNA expression were significantly decreased in the HF + NVD group. Conclusions: An inadequate vitamin D status was associated with greater hepatic lipid deposition, enhanced oxidative stress, and reduced hepatic SIRT1 activity, and lower expression of Nrf2-related antioxidant genes. These findings support that maintaining adequate vitamin D status might help preserve hepatic metabolic homeostasis during obesity. Full article

Background and Objectives: To propose an integrated qualitative and quantitative US strategy for improving the diagnostic accuracy of hepatic steatosis (HS) grading. Materials and Methods: We retrospectively identified patients at a tertiary hospital who underwent B-mode US examination, attenuation imaging (ATI), hepatorenal index (HRI), and liver biopsy on the same day between 2023 and 2024. B-mode liver US images were independently reviewed by three radiologists with varying levels of experience. Each radiologist qualitatively assessed the degree of HS using a three-tier grading system: (1) no HS, (2) mild HS, and (3) moderate/severe HS. Median attenuation coefficient (AC) and HRI values were recorded. Liver biopsy pathology reports were used as the reference standard. We evaluated four strategies integrating qualitative assessment with ATI or HRI and compared their diagnostic performance. Results: Based on B-mode US, accuracies for detecting HS by the three radiologists were 87.0%, 87.0%, and 86.0%, respectively; for moderate/severe HS, the values were 79.0%, 76.0%, and 71.0%. ATI and HRI alone yielded diagnostic accuracies of 83.0% and 81.0%, respectively, for any HS and 67.0% and 53.0%, respectively, for moderate/severe HS. The highest accuracy was achieved using a strategy that retained the qualitative grade for one-grade discrepancies and assigning the intermediate grade only for two-grade discrepancies between the AC-based grade and the qualitative grade (93.0%, 87.0%, and 90.0% for any HS; 80.0%, 76.0%, and 74.0% for moderate/severe HS). Conclusions: The proposed integration strategy, which retained the qualitative grade for one-grade discrepancies and assigned the intermediate grade only for two-grade discrepancies, improved or maintained diagnostic performance, regardless of the radiologist’s level of experience. Full article

An abnormality of Ca²⁺ signaling may aggravate lipid accumulation in steatotic hepatocytes, leading to non-alcoholic fatty liver disease. However, the molecular identity of Ca²⁺-permeable channels and the mechanism of involvement of these channels in steatotic hepatocytes are not well-studied. In the present study, we investigated the role of a Ca²⁺-permeable channel TRPM2 in lipid metabolism in steatotic hepatocytes. A mouse model of non-alcoholic fatty liver disease was established by high-fat-diet feeding. Fat accumulation, fibrosis, lipophagic indexes, TFEB and lysosomal acid lipase in the liver tissue and/or hepatocytes were compared between TRPM2-knockout mice and wild-type mice. Knockout of the TRPM2 gene aggravated liver fat accumulation and fibrosis. Mechanistically, the TRPM2 knockout impaired the lipophagic process, decreased lysosomal abundance and attenuated lysosomal/autolysosomal acidification in mouse hepatocytes. Furthermore, the TRPM2 knockout reduced TFEB expression and its nuclear translation and also reduced the expression/activity of lysosomal acid lipase. These data demonstrate that TRPM2 deficiency may reduce lipophagy via its action on TFEB and lysosomal acid lipase, consequently contributing to liver steatosis and NAFLD under high-fat feeding conditions. Full article

6PPD and its ozonation product 6PPD-quinone (6PPD-Q) are ubiquitous tire-derived pollutants linked to environmental and potential human health risks. This study systematically investigated their mechanisms in lipid-metabolism-related diseases (atherosclerosis, type 2 diabetes, and nonalcoholic fatty liver disease) through network toxicology, transcriptomic validation, molecular docking, and experimental models. Targets of 6PPD and 6PPD-Q were predicted using multiple databases and intersected with disease-associated genes. Protein–protein interaction networks, hub gene screening, GO/KEGG enrichment, and GEO transcriptomic datasets identified key shared core targets, including PTGS2, MMP9, CXCL8 (for 6PPD), MAPK14, and PTGS2 (for 6PPD-Q). Molecular docking suggested potential strong binding affinities. Integrative analysis highlighted convergence on oxidative stress, inflammation, lipid dysregulation, and MAPK signaling. In vivo, 40-day exposure to 6PPD and 6PPD-Q in C57BL/6 mice induced hepatic steatosis, elevated serum TC, LDL-C, and HDL-C, upregulated inflammatory cytokines (TNF-α, IL1B, IL6, and IFNG), and core targets. In vitro, both compounds caused dose-dependent cytotoxicity, ROS accumulation, glutathione redox imbalance, and pro-inflammatory activation. These findings suggest that 6PPD and 6PPD-Q may contribute to lipid-metabolism-related toxic responses through shared and distinct processes involving oxidative stress, inflammatory activation, and lipid dysregulation. These results provide preliminary mechanistic insights into their metabolic toxicity and support further experimental evaluation for environmental health risk assessment. Full article

Background: We aimed to investigate the prevalence of HSD17B13 polymorphisms while evaluating the correlation between HSD17B13 gene variants and NASH prevalence in the Taiwanese population. Furthermore, we tried to identify the diagnostic value of liver enzymes as non-invasive biomarkers for NASH in morbidly obese patients. Methods: Severely obese patients with non-alcoholic fatty liver disease (NAFLD) who received liver biopsy during bariatric surgery and controls of liver donors who underwent donor hepatectomy were enrolled from 2016 to 2021. Genotyping was utilized in TaqMan PCR assays. For comparison of NAFLD severity, patients were divided into no NASH (NAFLD activity score, NAS 0–2), borderline NASH (NAS 3–4), and NASH (NAS 5–8). Results: The proportion of HSD17B13 rs72613567 TA allele carriers (T/TA and TA/TA genotypes) was 96% in both groups, corresponding to an estimated TA allele frequency of approximately 50% based on a standard allele-counting method. Among morbidly obese patients, T/TA and TA/TA genotypes were associated with lower odds of NASH prevalence compared with T/T genotype. For the non-invasive predictive factors of NASH, NASH group had significantly higher level of liver enzymes compared to “no NASH” and “borderline NASH” groups. Receiver operating characteristic curve analysis revealed there were moderate predictive values for NASH in AST (AUC = 0.71, p = 0.014) and ALT (AUC = 0.73, p = 0.007). Conclusions: Our study revealed a relatively high prevalence of the loss-of-function TA variant of HSD17B13 in this southern Taiwanese cohort, irrespective of body weight. This variant may contribute to the comparatively lower prevalence of NASH in the region. Additionally, AST and ALT may have potential predictive value for NASH prevalence. Given the single-center design, further larger, population-representative studies are warranted. Full article

Background: Alcohol-associated fatty liver disease (AFLD) is a major public health concern and remains one of the leading causes of chronic liver disease in the United States. Understanding the interplay between obesity, metabolic dysfunction, and lifestyle factors may help identify populations at increased risk for AFLD. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2013–2018. AFLD was operationally defined using elevated liver enzyme levels combined with risky alcohol consumption. Metabolic obesity phenotypes (MOPs) were characterized by combining body mass index categories with either metabolic health status or metabolic syndrome (MS). Results: The weighted prevalence of AFLD was 14% (95%CI: 12–16%). AFLD prevalence was significantly higher among males than females (17% vs. 10% respectively, p < 0.0001), and among Hispanics compared to Non-Hispanic Black participants (20% vs. 9% respectively, p < 0.0001). Compared with metabolically healthy normal-weight individuals, obese participants with MS demonstrated the strongest association overall AFLD association (adjusted PR: 6.73; 95% CI: 4.51–10.05). Furthermore, obese males with MS showed the highest odds of AFLD under both MOP schemes (MOP 1: OR: 8.19; 95% CI: 4.41–15.23; MOP 2: OR: 10.92; 95% CI: 6.86–17.37). Conclusions: Individuals with obesity and metabolic dysfunction demonstrated significantly higher AFLD prevalence compared with metabolically healthy normal-weight individuals. MOPs incorporating MS demonstrated stronger associations with AFLD than classifications based on metabolic health status alone. These findings support the importance of screening strategies that address both obesity and metabolic dysfunction in addition to alcohol use to better identify high-risk populations. Full article

Background and Objectives: Renal sinus fat accumulation affects many diabetic processes, including blood pressure. The aim of this study was to find out if there is a link between the amount of fat in the renal sinus and the blood pressure that changes throughout the day in adults with non-alcoholic fatty liver disease (NAFLD). Materials and Methods: This retrospective analysis involved 55 adult patients diagnosed with non-alcoholic fatty liver disease (NAFLD) based on abdominal computed tomography (CT) and who had undergone 24 h ambulatory blood pressure monitoring (ABPM). According to standard ABPM criteria, individuals whose night-time systolic blood pressure decreased by ≥10% compared to daytime values were classified as “dippers,” whereas those with a reduction of <10% were classified as “non-dippers”. Results: The non-dipper group had a significantly higher leukocyte count (p = 0.012). Renal sinus fat volume (RSFV) was significantly larger in the non-dipper group (6.41 ± 3 mL) than the dipper group (4.12 ± 2.26 mL; p = 0.005). In the ROC curve analysis showing the role of RSFV in predicting the non-dipper blood pressure pattern, the threshold value for RSFV in our cohort was determined as ≥3.7 mL with a positive predictive value of 72.2%. Conclusions: Our findings indicated that RSFV plays a significant role in predicting the non-dipper blood pressure profile among individuals diagnosed with NAFLD. Participants with an RSFV of 3.7 mL or more in our cohort were more likely to exhibit a non-dipping blood pressure pattern. Future studies are needed to validate these findings in larger cohorts. Full article

The ever-increasing disparity between lifespan and healthspan represents a challenging global issue, with metabolic dysregulation playing a central role in the initiation and progression of chronic non-communicable diseases (NCDs). This review highlights the importance of maintaining optimal redox homeostasis, with particular emphasis on reduced glutathione (GSH), for preserving metabolic health during aging. GSH participates in several physiological processes, including antioxidant defense, xenobiotic detoxification, redox signaling, and metabolic regulation. Diminished GSH levels are consistently reported in obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver, and cardiovascular diseases. Current evidence from human clinical studies indicates that foods rich in bioactive constituents can enhance GSH levels and stimulate GSH-dependent enzyme activity, with the Nrf2/Are signaling pathway being a central mechanistic link. Fasting may promote adaptive redox responses by inducing mild oxidative stress and activating the same molecular mechanism, although the effects on GSH-related antioxidant mechanisms remain heterogeneous across fasting protocols and study populations. Altogether, the available clinical evidence suggests that these nutritional and lifestyle interventions exhibit more consistent beneficial effects in individuals characterized by increased oxidative burden and underlying metabolic dysfunction. Interindividual differences in GSH responses further underscore the need for targeted, tailor-made approaches that account for genetic, epigenetic, and lifestyle factors. Collectively, targeting GSH homeostasis through nutritional and lifestyle interventions represents a promising strategy for improving metabolic health and may further contribute to healthy aging, positioning redox biology at the forefront of aging research and NCD prevention. Full article

Phase transition or phase separation occurs in cells and tissues in many physiological events, such as protein granules (P granules) in early C. elegans development. Inappropriate phase transition is often associated with pathologic processes such as RNA–protein complex (RNP) and FUS-mutation-associated diseases. Given its ubiquity, phase transition has been considered a new frontier for comprehending physiological processes and pathological diseases. However, molecular and cellular mechanisms of phase transition in situ remain poorly described. Combining histochemistry with polarization analysis and biochemical thin-layer chromatography, we identified a massive phase transition change during the development of Taihe fowl (Gallus gallus domesticus Brisson). During embryonic day 12 (E12), the livers of these Silkie chicken demonstrated a sudden massive transition from hepatic lipid droplets (HLD) into hepatic liquid crystal droplets (HLCDs). We identified these changes by characterizing the sudden appearance of birefringent Maltese crosses (MCs) typical to liquid crystals (LC) where non-birefringent lipid droplets used to reside within hepatic cells. LC status was confirmed by fluidity with shape-changing and in vitro thermal phase transition tests. These HLCDs were present consistently until the early postnatal days after hatching. Using thin-layer chromatography combined with X-ray diffraction analysis, we determined that these HLCDs were composed of cholesterol, cholesterol ester and lecithin, which are the same as the components of cytoplasmic membrane. There was no change in the quantity of lipid components during liver development to suggest a critical mass of components triggering these changes. However, expressions of membrane-associated autophagy markers LC3A and Beclin 1 increased dramatically during this HLD to HLCD transition. Increases in membrane-associated LC3A and Beclin 1 are localized with massive increases in membrane lipid components of HLCDs. Areas with enhanced LC3A and Beclin 1 signaling have been associated with liquid crystal MCs to the thickness of 69 Å (Bragg d value). These associations indicate the possible regulatory role autophagy plays during liquid crystal phase transition in embryonic liver development. Reactivation of this autophagy pathway may be a possible mechanism behind the development of non-alcoholic fatty liver disease in adulthood. Full article

Palmitic acid (PA) can be used as a substitute for fish oil in aquaculture; however, excessive intake can easily cause lipotoxic liver damage in animals, and the progression of non-alcoholic fatty liver disease (NAFLD) is closely associated with it. Adult zebrafish (Danio rerio) share a high degree of genetic homology with humans and possess conserved lipid metabolism pathways, making them ideal model organisms for studying hepatic lipotoxicity. This paper presents a comprehensive narrative review of studies on PA-induced hepatic lipotoxicity, with a primary focus on the adult zebrafish model: it elucidates the morphological and functional abnormalities in liver tissue caused by PA exposure; explains the molecular mechanisms by which PA induces metabolic disorders and cellular stress through upregulation of lipid synthesis and inhibition of β-oxidation, which further activates inflammatory signaling pathways such as NF-κB/JNK and may ultimately contribute to liver fibrosis; and summarizes intervention strategies targeting these mechanisms. Studies using embryonic or larval zebrafish are included only as supplementary mechanistic evidence where adult data are unavailable and are clearly distinguished throughout the text. To ensure transparency, the literature search and screening process are reported in detail, although formal systematic review methodologies (e.g., PRISMA, dual independent screening, and quantitative risk-of-bias assessment) were not applied. This study aims to refine the evaluation system for PA-induced hepatic lipotoxicity, providing both theoretical support for the scientific application of PA in aquaculture and important references for elucidating the pathogenesis of human NAFLD/NASH and developing preventive and therapeutic measures. Full article

Background/Objectives: Many HIV-positive (HIV+) males receiving highly active antiretroviral therapy (HAART) experience metabolic complications, including non-alcoholic fatty liver disease (NAFLD); lipodystrophy; and intestinal dysbiosis, often characterized by a Prevotella-rich enterotype. Gut microbial fermentation produces short-chain fatty acids (SCFAs), which play important roles in host metabolism. This study investigated the relationships among HAART, anthropometrics, diet, intestinal permeability, gut microbiota composition, and lipodystrophy in HIV+ males. Methods: Forty males aged 23–60 years were enrolled, including 19 HIV+ participants recruited from the East Tennessee State University (ETSU) Health Infectious Diseases Specialty Clinic and 20 HIV-negative (HIV−) controls recruited through standard methods. Participants provided a stool sample for 16S rRNA gene sequencing, SCFA analysis by gas chromatography, and proximate analysis, and completed a food frequency questionnaire. Lipodystrophy-related measures included body mass index (BMI), hip-to-waist ratio (H:W), and liver health assessment using FibroScan. Blood samples were collected by venipuncture. Serum markers of intestinal permeability, including Claudin-21, flagellin, and intestinal fatty acid-binding protein (IFABP), were quantified by enzyme-linked immunosorbent assay (ELISA). Results: HIV+ males exhibited significantly higher H:W ratios (p = 0.001) and hepatic steatosis (p = 0.0047) than HIV− controls (Welsh’s t-test). Concentrations of isobutyrate (p = 0.0024), isovalerate (p = 0.0008), and valerate (p = 0.0329) were elevated in HIV+ participants, whereas butyrate (p = 0.0014) and total acetate/propionate/butyrate (APB) (p = 0.0046) were higher in HIV− males (Welsh’s t-test). HIV+ participants also showed greater abundances of Prevotella and Lachnospiraceae (Analysis of Compositions of Microbiomes; ANCOM). Retrospective analysis revealed that all HIV+ participants were men who have sex with men (MSM). Conclusions: HIV+ males demonstrated distinct gut microbiome profiles, altered SCFA production, and markers of disrupted lipid metabolism. These findings provide a foundation for future investigations of microbiome-metabolism interactions in HIV+ MSM. Full article

Background: Nutrition and nutrition-related interventions are a salient yet under-recognized component of preventing the development of and complications of metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, malnutrition affects a significant proportion of patients with MASLD, yet remains under-treated in the primary care setting. The objective of this narrative review is to synthesize the available evidence regarding nutritional screening, diet, and supplements in patients with MASLD. This review is aimed at primary care physicians to improve the recognition of malnutrition in MASLD patients and provide appropriate nutritional guidance. Methods: Between November 2025 and June 2026, the authors conducted a literature review using the PubMed database. Search terms included combinations of the following: MASLD, non-alcoholic fatty liver disease (NAFLD), malnutrition, sarcopenia, nutritional screening, Mediterranean diet, micronutrients, and physical activity. Randomized controlled trials (RCTs), systematic reviews, and meta-analyses addressing nutritional outcomes in liver disease were prioritized, and consensus guidelines were incorporated where primary trial evidence was limited. Evidence was appraised by study design, risk of bias, and endpoint; recommendations resting on expert opinion or extrapolation from cirrhosis populations are identified as such. Results: Author review of the studies yielded the following conclusions. Nutritional assessment should be risk-stratified by fibrosis stage using liver disease-specific tools, as BMI and body weight are unreliable in MASLD. Weight loss has been shown to improve histological and clinical progression in MASLD. The Mediterranean diet has the strongest support for steatosis reduction among the dietary interventions discussed. Coffee consumption is consistently associated with reduced fibrosis risk in observational data, but no randomized evidence exists. GLP-1 receptor agonists achieve histological MASH resolution in up to 63% of patients but require concurrent nutritional monitoring to mitigate lean mass loss. Systemic barriers, including time constraints and limited dietitian access, remain the primary impediment to primary care implementation. Conclusions: Primary care physicians are central in managing many aspects of care for patients with MASLD. This review highlights the established evidence behind diet, exercise and malnutrition prevention in the primary care setting. Full article

Background and Objective: Non-alcoholic fatty liver disease (NAFLD) induces systemic low-grade inflammation and lipotoxicity. While its microvascular effects on the inner ear are recognized, its impact on the middle ear remains unexplored. This study aimed to investigate subclinical biomechanical alterations in the middle ear of normal-hearing NAFLD patients using Wideband Tympanometry (WBT). Materials and Methods: This prospective observational study included 28 patients with ultrasonographically confirmed NAFLD and 30 healthy, sex-matched controls. All included participants had normal pure-tone hearing thresholds and Type A tympanograms. WBT was performed to measure Resonance Frequency (RF) and frequency-specific absorbance (226–8000 Hz). A subgroup analysis compared early-stage (Grade 1) and advanced-stage (Grades 2–3) hepatosteatosis. Results: The mean RF was significantly lower in the NAFLD group compared to the controls for both the right (781.6 ± 218.7 vs. 1010.6 ± 529.0 Hz; p = 0.035) and left ears (740.3 ± 212.7 vs. 1221.6 ± 754.2 Hz; p = 0.002). Furthermore, wideband absorbance was significantly elevated at lower frequencies (250 Hz and 500 Hz) in the study group (p < 0.001 for both ears). Middle ear resting pressures were similar between the groups. Subgroup analysis revealed no significant differences in WBT parameters between Grade 1 and advanced stages (p > 0.05). Conclusions: Normal-hearing NAFLD patients exhibit a mass-dominated biomechanical shift in the middle ear, characterized by a decreased RF and increased low-frequency absorbance. These subclinical alterations, observable even in early-stage hepatosteatosis, likely reflect mucosal micro-edema driven by systemic inflammation. WBT serves as a sensitive, non-invasive tool for detecting early metabolic-related otologic changes. Full article

Background: Type 2 diabetes mellitus (T2DM) is associated with subclinical myocardial dysfunction, which may occur despite preserved left ventricular ejection fraction. Left ventricular global longitudinal strain (LV GLS) is a sensitive marker of early systolic impairment and may detect subtle changes in myocardial function before conventional echocardiographic parameters become abnormal. The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on LV GLS in adults with T2DM remains incompletely defined. Objective: To synthesize the available evidence on the effects of SGLT2i therapy on LV GLS or LV strain in adults with T2DM. Methods: Original full-text human studies evaluating SGLT2i therapy in adults with T2DM and reporting LV GLS or LV strain were included. LV GLS was assessed primarily by speckle-tracking echocardiography, while one study used cardiac magnetic resonance feature-tracking. Reviews, conference abstracts, protocols, animal-only studies, and studies without LV strain assessment were excluded. Risk of bias was assessed using RoB 2 for randomized studies and ROBINS-I for non-randomized studies. Results: Twenty-six studies involving more than 2300 participants were included. The studies evaluated dapagliflozin, empagliflozin, ertugliflozin, canagliflozin, or mixed SGLT2i regimens across heterogeneous clinical populations, including patients with preserved ejection fraction, pre-heart failure, diabetes-related cardiomyopathy, chronic heart failure, coronary artery disease, hypertension, non-alcoholic fatty liver disease, and cardio-oncology risk. Most observational and before–after studies reported favorable changes in LV GLS after SGLT2i therapy, whereas randomized and controlled studies showed more variable findings. Several studies also reported improvements in LV remodeling, diastolic function, left atrial function, myocardial work indices, NT-proBNP, cardiometabolic parameters, or epicardial adipose tissue thickness. However, the certainty of evidence was limited by methodological heterogeneity, differences in comparator groups, variable follow-up duration, non-standardized imaging protocols, and risk of bias, particularly in non-randomized and single-arm studies. Conclusions: SGLT2i therapy may be associated with favorable changes in LV GLS in adults with T2DM, suggesting a potential beneficial effect on subclinical left ventricular systolic function. However, current evidence does not definitively establish a consistent treatment effect across all populations. Larger randomized controlled trials with standardized strain imaging protocols, predefined LV GLS endpoints, and clinically relevant follow-up are needed to determine whether SGLT2i-related improvements in LV GLS reflect true myocardial benefit and translate into improved cardiovascular outcomes. Full article