Search Results (1,223)

Background/Objectives: This study evaluated whether yoghurt containing Apilactobacillus kunkeei DSM 12361 protects rats against non-alcoholic fatty liver disease (NAFLD). We hypothesized that this fructophilic probiotic, with anti-inflammatory properties, may affect NAFLD progression by improving the gut microbiome, lowering intestinal ethanol production, and modulating inflammatory and metabolic pathways linked to hepatic fat accumulation. Methods: Wister rats were randomized into three groups; rats in the control group (HFrD) were fed a high-fructose (70%) diet while rats in experimental groups were fed the same diet mixed with 10% of yoghurt containing YC-180 starter culture (HFrD-Y) or yoghurt containing YC-180 and Apilactobacillus kunkeei DSM 12361 (HFrD-Y-A). Results: After six weeks of intervention, levels of plasma triglycerides, cholesterol, glucose, liver enzymes (ALT and AST), interleukin (IL)-6, fecal ethanol, Enterobacteriaceae, and hepatic index were significantly increased (p < 0.05) in the HFrD group as compared to rats in both experimental groups. Moreover, plasma levels of liver enzymes, lipid profile, glucose, and IL-6 were significantly lower (p < 0.05) in rats of the HFrD-Y-A group than those in the HFrD-Y group. Furthermore, plasma levels of IL-10 and fecal Lactobacilli and Bifidobacteria were significantly increased (p < 0.05) in the experimental groups when compared to rats in the control group. Conclusions: In sum, the obtained results indicated that yoghurt containing Apilactobacillus kunkeei could decrease the risk of non-alcoholic fatty liver disease (NAFLD) through (a) blocking the inflammation process associated with NAFLD, (b) enhancing the lipid profile, (c) lowering fecal ethanol, and (III) decreasing the levels of fecal Enterobacteriaceae in comparison with levels of fecal Lactobacilli and Bifidobacteria in rats. More research on molecular mechanisms of the potential effects of the Apilactobacillus kunkeei strain against NAFLD is still required. Full article

The hepatic lymphatic system, long underappreciated, plays a critical role in liver physiology by maintaining interstitial fluid balance, removing metabolic waste, and facilitating immune surveillance. Emerging evidence indicates that lymphatic dysfunction contributes to the pathogenesis and progression of multiple liver diseases, including non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes current knowledge on hepatic lymphatic anatomy, physiology, and molecular regulation, highlights pathological alterations, and discusses potential therapeutic implications. A better understanding of the hepatic lymphatic system may enable the development of novel lymphatic-targeted strategies to improve liver health and treat liver disease. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease worldwide. MASLD spans a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and is linked to progressive fibrosis and ultimately hepatocellular carcinoma (HCC). Growing evidence implicates cellular senescence (CS) and lipid droplets (LDs) as key drivers of disease progression, although their interaction remains poorly characterized. This review provides an integrative and stage-dependent synthesis of current mechanistic insights into how bidirectional crosstalk between CS and LD regulation shapes the transition from steatosis to MASH. Senescent hepatocytes display altered lipid metabolism, including upregulation of receptors such as cluster of differentiation (CD) 36, enhancing lipid uptake to meet increased energy demands. Initially, elevated free fatty acid influx can activate peroxisome-proliferator-activated receptor alpha (PPARα), promoting fatty acid oxidation (FAO) as a compensatory response. Over time, persistent CS under steatotic conditions leads to mitochondrial dysfunction and suppression of fatty acid oxidation (FAO), while the senescence-associated secretory phenotype (SASP), largely driven by nuclear factor—kappa B (NF-κB) signaling, promotes chronic hepatic inflammation. By framing LDs as active modulators of senescence-associated signaling rather than passive lipid stores, this review highlights how disruption of senescence–lipid feedback loops may represent a disease-modifying opportunity in MASLD progression. Full article

Background: Depression and Metabolic Dysfunction-Associated Steatotic Fatty Liver Disease (MASLD) are common chronic diseases, respectively. However, the causal and molecular links between them remain unclear. In order to explore whether depression contributes to an increased risk of MASLD and whether inflammation mediates this effect, we integrated multi-level evidence from the epidemiology of the National Health and Nutrition Examination Survey (NHANES), the genetics of GWAS, the transcriptomes of GEO, and single-cell RNA sequencing datasets. Methods: A multi-level integrative analysis strategy was used to validate this pathway. First, a cross-sectional epidemiological analysis based on NHANES data was used to reveal the association between depression and MASLD, and to explore the mediating role of inflammation and liver injury markers. Secondly, a two-sample Mendelian randomization analysis was used to infer the causal direction of depression and MASLD, and to verify the mediating effect of systemic inflammation and liver injury indicators at the genetic level. Then, the transcriptome co-expression network analysis and machine learning were used to screen the common hub genes connecting the two diseases. Finally, single-cell transcriptome data were used to characterize the dynamic expression of potential key genes during disease progression at cellular resolution. Results: Depression significantly increased the risk of MASLD, especially in women (OR = 1.39, 95%CI [1.17–1.65]). Parallel mediation analysis showed that high-sensitivity C-reactive protein (hs-CRP) (p < 0.001), γ-glutamyltransferase (GGT) (p < 0.001), and alkaline phosphatase (ALP) (p < 0.001) mediated this relationship. Mendelian randomization analysis confirmed the unidirectional causal effect of depression on MASLD, and there was no reverse association (β = 0.483, SE = 0.146, p = 0.001). Weighted gene co-expression network analysis and machine learning identified CD40LG as a potential molecular bridge between depression-associated immune modules and MASLD. In addition, single-cell data analysis revealed a stage-specific trend of CD40LG expression in CD4⁺ T cells during MASLD progression, while its receptor CD40 was also activated in B cells. In the female sample, CD40LG maintained an upward trend. However, the stability of this result is limited by the limited sample size. Conclusions: This study provides converging multi-omics evidence that depression plays a causal role in MASLD through inflammation-mediated immune signaling. The CD40LG-CD40 axis has emerged as an immune mechanism that transposes depression into the pathogenesis of MASLD, providing a potential target for the intervention of gender-specific metabolic liver disease. Full article

Purpose: To investigate associations between lipid oxidation biomarkers (oxylipins), antioxidant micronutrients, lipoprotein particles, and apolipoproteins in multiple sclerosis (MS). Methods: Blood and neurological assessments were collected from 30 healthy controls, 68 relapsing remitting MS subjects, and 37 progressive MS subjects. Hydroxy (H) and hydroperoxy lipid peroxidation products of the polyunsaturated fatty acids (PUFAs) arachidonic (20:4, ω-6), linoleic (octadecadienoic acid or ODE, 18:2, ω-6), eicosapentaenoic (20:5, ω-3), and α-linolenic (18:3, ω-3) acids were measured using liquid chromatography–mass spectrometry. Antioxidant micronutrients, including β-cryptoxanthin and lutein/zeaxanthin, were quantified by high-performance liquid chromatography. Lipoprotein and metabolite profiles were obtained using nuclear magnetic resonance spectroscopy. Regression models were adjusted for age, sex, body mass index, and disease status. Results: The 9-hydroxy octadecadienoic acid to 13-hydroxy octadecadienoic acid ratio (9-HODE/13-HODE ratio), which reflects autoxidative versus enzymatic oxidation, was associated with MS status (p = 0.002) and disability on the Expanded Disability Status Scale (p = 0.004). Lutein/zeaxanthin (p = 0.023) and β-cryptoxanthin (p = 0.028) were negatively associated with the 9-HODE/13-HODE ratio. Apolipoprotein-CII, a marker of liver-X-receptor (LXR) signaling, was associated with 9-HODE/13-HODE ratio and other oxylipins. Octadecadienoic fatty acid-derived oxylipins were negatively associated with LC3A, a mitophagy marker, and positively correlated with 7-ketocholesterol, a cholesterol autoxidation product. Conclusions: Autoxidation of PUFAs is associated with greater disability in MS. Higher β-cryptoxanthin and lutein/zeaxanthin were associated with reduced auto-oxidation. Lipid peroxidation shows associations with LXR signaling, mitophagy, inflammation, and cholesterol autoxidation. Full article

Background/Objectives: Sex-specific differences in metabolic dysfunction-associated fatty liver disease (MAFLD)-related hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to clarify sex-associated disparities in disease progression and recovery using a diethylnitrosamine (DEN) plus Western diet/fructose-induced murine model combined with artificial intelligence (AI)-assisted histological analysis. Methods: Male and female C57BL/6J mice received a single diethylnitrosamine injection and were fed a Western diet/fructose regimen for 38 weeks, followed by an 8-week recovery period on standard chow. Serum biochemical parameters were measured, and liver histology was assessed using second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy. Steatosis and fibrosis were quantified within tumor and adjacent non-tumor regions using AI-based image analysis. Results: Male mice developed more severe disease phenotypes, including greater tumor burden and higher serum alanine aminotransferase levels, compared with females. Following dietary recovery, female mice showed substantial reductions in tumor number and hepatic steatosis, particularly in non-tumor regions; in contrast, male mice demonstrated only minimal improvement. AI-assisted quantification confirmed considerable regression of both steatosis and fibrosis in females and moderate fibrosis improvement in both sexes. Conclusions: These findings indicate sexual dimorphism in the progression and regression of MAFLD-related HCC, with females exhibiting enhanced metabolic and histological recovery. The results underscore the importance of considering sex as a biological variable in preclinical metabolic dysfunction–associated fatty liver disease-related hepatocellular carcinoma research and highlight the value of AI-enhanced imaging for precise, objective evaluation of liver histology. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a highly prevalent hepatic condition closely linked to metabolic syndrome (MetS). Epigenetic regulators such as microRNAs (miRNAs) have emerged as critical modulators of the molecular pathways underlying MASLD pathogenesis, offering new perspectives for non-invasive diagnosis and targeted therapy. This study aimed to identify and characterize target genes and pathways regulated by two key hepatic miRNAs, namely miR-122 and miR-29a, through a comprehensive in silico bioinformatics approach, to better understand their functional roles in MASLD and MetS. Methods: Target genes of miR-122 and miR-29a were predicted using three databases (TargetScan, DIANA-microT-CDS, and miRWalk), and those identified by at least two databases were selected for downstream analyses. Functional enrichment was performed using Gene Ontology and KEGG pathway analysis. Gene networks and biological process maps were constructed using Metascape, clusterProfiler and Cytoscape. Results: miR-122 was found to negatively regulate genes involved in lipid metabolism, insulin signaling, and inflammatory pathways, including PPARGC1A, PPARA, LPL, TLR4, and HMGCR, contributing to insulin resistance and liver dysfunction. By contrast, miR-29a demonstrated potential hepatoprotective effects by targeting LEP, INSR, IL13, and IL18, enhancing insulin sensitivity and reducing fibrogenic activity. Enrichment analysis revealed strong associations with biological processes, such as STAT phosphorylation, lipid homeostasis, and inflammatory signaling, as well as associations with cellular components, including lipoproteins and plasma membranes. miR-122 and miR-29a exhibit opposing regulatory functions in MASLD pathogenesis. Whereas miR-122 is associated with disease progression, miR-29a acts protectively. These miRNAs may serve as promising biomarkers and therapeutic targets in MASLD and related metabolic conditions. Further validation through experimental and clinical studies is warranted. Full article

Background: High-fat or high-fructose consumption may cause abnormal lipid accumulation in the liver, resulting in fatty liver disease, and the intervention of other stress factors may accelerate the progression of this condition. Many studies have demonstrated that long-term exposure to blue light may not only injure the eyes but also cause an increase in oxidative stress, which has been related to metabolic and gut microbiota disorders. However, current research on whether blue light exposure exacerbates fatty liver disease still remains limited. Objective: Therefore, the aim of this study is to investigate the effect of a high-fat, high-fructose diet combined with blue light exposure on fatty liver disease progression. Method: In the first part of the study, we observed that 16 weeks of blue light exposure alone did not achieve significant effects in the liver of male, female, or OVX mice. Therefore, in the second part, we fed ICR mice a high-fat, high-fructose (HFHF) diet to investigate the effect of simultaneous 16-week exposure to blue light. The mice were assigned to three groups, control group (C), HFHF diet group (H), and HFHF diet plus blue light exposure group (HB), to investigate the intervention of unhealthy diet composition and blue light exposure on hepatic oxidative and inflammatory makers and gut microbiota composition. Results: The results showed that exposure to blue light exacerbates oxidative stress (hepatic MDA, p < 0.009), and inflammatory damage (lobular inflammation score, p < 0.0001; hepatic TNF-α, p = 0.0074) caused by an HFHF diet, but this mechanism is not mediated by the TLR4 signaling pathway. Furthermore, exposure to blue light may also partially affect the composition of the gut microbiota. Conclusions: The results of the study suggested that under unhealthy dietary conditions, long-term blue light exposure may be one of the risk factors accelerating the progression of fatty liver disease. Full article

Background: The transition from the term non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD), an umbrella term for several related conditions, offers benefits, particularly in identifying cardiometabolic risk factors more effectively. However, the impact of alcohol consumption on liver disease progression remains significant, leading to the recognition of a new entity: MetALD (metabolic dysfunction-associated steatotic liver disease with moderate alcohol intake). Aim: This study aimed to compare characteristics associated with liver disease progression in diabetic patients diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD) versus those with MetALD. Materials and Methods: In this prospective study, 286 diabetic patients were followed for 12 months. All patients underwent transient elastography (TE) and ultrasound to assess hepatic steatosis. Participants were classified into MASLD and MetALD groups. The performance of fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) were also evaluated. Results: MASLD was diagnosed in 58.2% (167 patients), of whom 4.9% (7 patients) had TE values suggestive for liver cirrhosis. Among those with MetALD, 17.6% (21 patients) had TE values compatible with advanced fibrosis. MASLD subjects presented a slight decrease in liver fibrosis values from 6.58 ± 2.27 kPa to 6.03 ± 1.57 kPa in the 12 months. On the contrary, MetALD subjects had an increase of liver stiffness measurements (LSM) values from 11.83 ± 6.27 kPa to 12.24 ± 8.66 kPa. Conclusions: in diabetic patients, the coexistence of moderate alcohol intake and cardiometabolic risk factors (MetALD) is associated with more advanced liver fibrosis and impaired long-term glycemic control, compared to MASLD alone. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become highly prevalent worldwide, and its pathogenesis and progression mechanisms remain incompletely understood. An increased activation of innate immune cells in the liver contributes to hepatic fibrogenesis via a chronic loop of inflammation and regeneration processes. Among them are mast cells (MCs), whose role in hepatic cirrhosis secondary to MASLD remains poorly studied. Our aim was to evaluate differences in MC density in cirrhotic liver tissue among patients with MASLD and other chronic liver disease etiologies. For this, a retrospective study of MC count was performed in cirrhotic liver explants obtained from MASLD, alcohol-related liver disease (ALD), and autoimmune hepatitis (AIH). We included a control group of subjects without liver damage. Tryptase-positive MCs were identified by indirect immunofluorescence and quantified as MC density per low-power field (MC/LPF). Group differences were analyzed using the Kruskal–Wallis test with Dunn’s multiple comparisons, considering p < 0.05 as statistically significant. A significantly higher MC density was observed in MASLD, ALD, and AIH patients compared with the control group. The group analysis showed that ALD patients exhibited higher MC density than AIH, with no observed difference between ALD and MASLD. MC density was correlated positively with tobacco smoking and alcohol use in the full analyzed group, suggesting them as risk factors of high MC liver infiltration. We conclude that MC density is augmented in MASLD-related cirrhosis, highlighting potential links between lifestyle factors and MC-mediated hepatic inflammation. Future studies should explore the mechanisms driving this association and evaluate whether targeting MCs could help mitigate fibrosis progression. Full article

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by abnormal lipid metabolism. The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in regulating multiple physiological processes. Recent studies have demonstrated that AHR exerts a multifaceted regulatory role in liver diseases by integrating metabolic and immune signaling pathways; however, the specific role of AHR in MAFLD is not clear. In our work, a rat model of MAFLD was established by feeding wild-type (WT) and AHR knockout (AHR^−/−) rats with a high-fat, high-fructose, and high-cholesterol diet (HFHFrHCD) for 10 weeks, and then the liver injury markers, lipid-related biochemical indices and liver histopathology were examined to elucidate the effect of AHR on MAFLD progression. We discovered that AHR deficiency can elevate plasma transaminase levels, increase hepatic triglyceride (TG) and total cholesterol (TC), and exacerbate insulin resistance (IR) under an overnutrition environment. Subsequently, liver transcriptome and RT-qPCR were performed to investigate the underlying mechanism, which revealed that the hepatic bile acid synthesis was inhibited because of lower Cytochrome P450 Family 7 Subfamily A Member 1 (CYP7A1) expression in the liver when AHR was knockout. Additionally, intestinal flora dysbiosis occurred in AHR^−/− rats fed with HFHFrHCD, which might also contribute to the hepatic cholesterol accumulation. Taken together, our results suggested that AHR might play an important role in regulating cholesterol metabolism by inhibiting bile acid synthesis and breaking the steady state of the gut microbiota during the MAFLD progression. Full article

Alzheimer’s disease (AD) is marked by cognitive decline, and also by retinal degeneration. Having in mind that docosahexaenoic acid (DHA, 22:6n − 3) is a safe, low-cost, and pivotal fatty acid for brain health and sustained cognitive function, this study exploits environmentally friendly non-fish sources as potential dietary supplements enriched with DHA to prevent or reverse AD. Forty 5xFAD transgenic male mice, aged five weeks old, were randomly distributed by five body weight-matched dietary groups (with eight animals each) and fed isocaloric diets based on the AIN-93M standard formulation for rodents for 6 months. Except for the control feed (without supplementation), each diet contained a modified lipidic fraction supplemented with 2% of the following: (1) linseed oil (LSO, rich in alpha-linolenic acid (ALA, 18:3n − 3)); (2) cod liver oil (fish oil, FO, rich in both DHA and eicosapentaenoic acid (EPA, 20:5n − 3)); (3) Schizochytrium sp. microalga oil (Schizo, with 40% of DHA); and (4) commercial DHASCO (DHASCO, with 70% of DHA). The aim of this study was to measure retinal neural layer thickness, calculate ganglion cell layer (GCL) density, and assess retinal injury by means of immunohistochemical staining for β-amyloid plaques deposition, TAU protein levels, and IBA1, as hallmark features of AD progression, in order to elucidate the effects of different dietary DHA treatments in Alzheimer’s retinas. Although no statistical differences were observed across retinal layer thicknesses depending on the diet (p > 0.05), there was a consistent pattern for slightly increased retinal thickness in 5xFAD mice fed fish oil relative to the others for the measurement of total layers, in general and for the inner segment/outer segment layer, the outer nuclear layer, the outer plexiform layer, the inner nuclear layer, and the inner plexiform layer, in particular. The ganglion cell layer (GCL) density was increased in 5xFAD mice fed the DHASCO oil diet relative to the control (p < 0.05), suggesting a benefit of DHA supplementation on the number of viable ganglion cells. No positive staining was observed for β-amyloid plaques deposition or the neuroinflammatory marker, IBA1, corroborating previous findings in human AD retinas. Conversely, the internal retinal layers showed intense TAU immunostaining. Immnunostained TAU area was significantly reduced in 5xFAD mice fed a fish oil diet compared to control (p < 0.05), although the number of TAU-positive cells did not differ across diets (p > 0.05). The retinal protected integrity derived from the benefits of DHA supplementation found, either from fish oil or DHASCO oil, underscores the potential of retinal biomarkers as non-invasive indicators of cognitive decline and overall brain health, opening new avenues for investigating AD pathophysiology in the retina. Full article

The absence of a unifying pathogenetic mechanism in metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has significantly hindered therapeutic progress. Appreciation that the delivery of excessive amounts of calories to the liver via the portal circulation might be a key parallel between MASLD and the twin steatotic liver disease, alcohol-related liver disease (ALD), establishes a consolidated framework that could guide rational drug design and precise therapeutic approaches. This review contends that, in both ALD and MASLD, the unique dual blood supply to the liver, from both portal vein and hepatic artery as well as the distinctive blood flow control physiology, prevents hepatic arterial oxygen delivery from adequately compensating for the increased metabolic demands induced by excess caloric intake—alcohol in ALD and food in MASLD—resulting in hepatocellular injury. Over four decades ago, Lautt postulated that this ‘oxygen-nutrient mismatch’ could play a role in ALD. We have extended this paradigm to MASLD, theorizing that analogous mechanisms may be involved in both conditions. Evidence that comorbidities, which are associated with recurrent episodes of hypoxemia, such as obstructive sleep apnea (OSA), exacerbate MASLD progression, supports this. ALD is less strongly linked to metabolic syndrome than MASLD. This may be due to inherent differences in hepatic substrate processing. Carbohydrates, lipids, and proteins undergo diverse and flexible cytosolic metabolic pathways, especially under metabolic stress. In contrast, hepatic ethanol metabolism is predominantly linear and obligately oxidative, providing limited metabolic adaptability. Future perspectives could focus on rectifying the imbalance between hepatic oxygen delivery and nutrient availability. This might be accomplished by attenuating hepatic caloric excess using emerging pharmacotherapies for weight reduction, augmenting hepatic oxygenation through hyperbaric oxygen therapy, or increasing hepatic arterial blood flow with agents such as obeticholic acid. Furthermore, enhancement of hepatic basal metabolic activity with thyroid hormone receptor-β agonists, like resmiritom may confer similar therapeutic effects. Full article

The global population is aging rapidly and the prevalence of age-related noncommunicable diseases is increasing. Favorable dietary patterns have the power to reduce the risk or progression of various age-related chronic diseases, including obesity, hypertension, cardiovascular disease, type 2 diabetes, several types of cancer, and some neurodegenerative diseases. In contrast, adverse dietary patterns may contribute to the onset or progression of many chronic diseases or their risk factors. A diet rich in wholesome, nutrient-dense, minimally processed foods, such as a Mediterranean-style diet, may promote health and prevent disease through its abundance of antioxidants, fiber, omega-3 fatty acids, and micronutrients. Conversely, a diet high in nutrient-poor and ultra-processed foods may accelerate disease onset and progression by promoting inflammation and affecting metabolic pathways adversely. This narrative review summarizes the literature from clinical trials and large population-based studies on protective dietary patterns and adverse dietary patterns that influence risk of cardiovascular disease and related risk factors, cancer, Alzheimer’s disease and related dementias, type 2 diabetes, frailty, and liver disease. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease worldwide, with an increasing prevalence, mainly due to the increase in childhood obesity and sedentary lifestyle. The pathogenesis of NAFLD is multifactorial, but the mechanisms by which the factors involved, namely the genetic, intrauterine and environmental factors responsible for its onset and progression to NASH, are not fully known. Children with NAFLD are usually asymptomatic or show nonspecific symptoms, and NAFLD is generally diagnosed incidentally by screening tests in overweight or obese children. NAFLD is associated with severe metabolic deficiencies that may progress to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Current treatment of NAFLD in children consists of lifestyle changes to decrease caloric intake and increase physical activity, with no currently approved pharmacological medication for the pediatric population. Although pediatric studies that focus on alternative treatments targeting key pathogenic factors are promising, no pharmacological agent is currently approved for children, validated non-invasive fibrosis biomarkers remain limited, and long-term outcome data are scarce. Further validation through large prospective pediatric cohorts and phase III trials is urgently needed. Full article