Search Results (738)

Diseases such as obesity and metabolic-dysfunction-associated fatty liver disease (MAFLD) are often associated with changes in gut microbiota composition. The present study aims to investigate the relationship between the potential preventive effects of an Opuntia ficus-indica var. colorada cactus pulp extract on obesity and hepatic steatosis, and changes in gut microbiota composition, in a murine model fed a high-fat high-fructose diet. The low-dose extract was the most effective in reducing hepatic TG (−12.5%) and the weight of subcutaneous and visceral adipose tissue (−18.4% and 11.4%, respectively), while the high dose led to improved serum lipid profile (−74.2% in TG, −37.2% in total cholesterol, −50.5% in non-HDL cholesterol and +71.7% in HDL cholesterol). Opuntia extract supplementation did not prevent the dysbiosis in gut microbiota produced by the high-fat high-fructose diet. However, modifications in its composition, consistent with an increment in both Adlercreutzia muris and Cutibacterium acnes, and a reduction in Massiliimalia timonensis, were observed. It can be proposed that these changes may contribute to the extract effects against obesity and liver steatosis. Nevertheless, further research is required to establish a direct link between the anti-obesity and anti-steatotic effects and the functionality of the bacteria modified by the treatment. Full article

The peptide hormone kisspeptin, signaling via its receptor, KISS1R, decreases hepatic steatosis and protects against metabolic dysfunction-associated steatotic liver disease (MASLD). Enhanced de novo lipogenesis (DNL) contributes to MASLD. Here, we investigated whether kisspeptin treatment in obese, diabetic mice directly attenuates DNL. DNL was assessed in kisspeptin-treated mouse livers, using a mouse model of MASLD, (DIAMOND mice), employing ²H₂O-enriched water, mass spectrometry analysis, and transcriptomic profiling. Gene and protein expression were evaluated in primary hepatocytes and livers. Additionally, hepatic Kiss1r expression was increased in DIAMOND mice, following which various biochemical and metabolic assessments were employed. Metabolic tracing in kisspeptin-treated steatotic livers demonstrated a decrease in the DNL of free fatty acids (FFAs), known to be associated with diabetes, steatosis, and hepatocellular carcinoma. Transcriptomic profiling of kisspeptin-treated livers identified disruption of key metabolic pathways, the most prominent being a decrease in fatty acid metabolism, and downregulation of Cidea, a key regulator of lipid droplet formation. Kisspeptin treatment of FFA-loaded primary mouse hepatocytes significantly decreased Cidea expression. Mechanistically, we found that kisspeptin administration decreased levels of transcription factor SREBP-1c, a crucial regulator of DNL, and CIDEA. Thus, enhanced KISS1R signaling limits hepatic DNL, suggesting a crucial role in restricting MASLD. Full article

Obesity and associated metabolic disorders are rising globally, necessitating effective dietary strategies. CKDB-322, a formulation containing Lactiplantibacillus plantarum Q180 and Phaeodactylum tricornutum, was evaluated for anti-obesity efficacy using in vitro adipocyte differentiation and in vivo high-fat-diet (HFD)-induced obese mouse models. In 3T3-L1 cells, CKDB-322 suppressed adipogenesis by downregulating PPARγ and C/EBPα and enhancing glycerol release. In mice, 8 weeks of oral administration—particularly at the CKDB-322-M dose—significantly reduced body weight gain, adiposity, and serum glucose, triglyceride, and cholesterol levels without affecting liver function. Gene expression analysis revealed the strong inhibition of lipogenic markers (SREBP-1c, ACC, and FAS) in addition to activation of the fatty acid oxidation (CPT-1α and PPARα) and energy metabolism (PGC-1α and AMPK) pathways, with the most pronounced effects in the CKDB-322-M group, which also exhibited the greatest reduction in leptin. These molecular effects were confirmed histologically by decreased adipocyte hypertrophy and ameliorated hepatic steatosis. Collectively, these findings demonstrate that CKDB-322 exerts lipid-modulatory effects through multiple pathways, supporting its potential as a novel functional dietary ingredient for obesity and metabolic disorder prevention. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)—an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention. Full article

Background/Objectives: Nicotine-free electronic cigarettes (NFECs) are becoming increasingly popular, especially among youth and non-smokers, yet their effects on the gastrointestinal tract (GIT) remain poorly understood. This systematic review synthesizes available in vitro, in vivo, and limited human evidence on NFEC-associated changes in gastrointestinal health and function. Methods: Literature searches were conducted in Medline, Web of Science, Cochrane, and Scopus in July 2025, following PRISMA guidelines. Eligible studies examined NFEC effects on any GIT segment, including the oral cavity, liver, intestines, and microbiome. Data on study design, exposure characteristics, and main outcomes were extracted and narratively synthesized. Results: Of 111 identified records, 94 full-text articles were retrieved, and 21 studies met the inclusion criteria. Most were preclinical, with only one human pilot study. Evidence from oral cell and microbial models suggests that NFEC aerosols can induce pro-inflammatory cytokine production, impair cell viability, and disrupt microbial metabolism through their base constituents (propylene glycol, vegetable glycerine, and flavourings). Animal studies indicate possible hepatic oxidative stress, altered lipid metabolism, and gut barrier dysfunction, with some data suggesting more pronounced steatosis in nicotine-free exposures compared to nicotine-containing counterparts. Microbiome studies report reduced tight junction expression and altered neutrophil function. Conclusions: Current evidence is limited and predominantly preclinical but indicates that NFEC exposure can affect multiple aspects of gastrointestinal health. Robust longitudinal and interventional human studies are urgently needed to determine the clinical relevance of these findings and to inform regulation and public health policy. Full article

This study investigated the anti-obesity effects of a homogenized, viscous vegetable (VV) mixture prepared from mucilaginous vegetables, with a focus on modulating hepatic lipid metabolism and gut microbiota composition in mice fed with a high-fat (HF) diet. The VV mixture was formulated by blending freeze-dried powders of ten mucilaginous vegetables, classified as moderately thick using a line-spread test and extremely thick according to the IDDSI framework in a 1:9 ratio (VV mixture: water, w/w). Six-week-old male C57BL/6 mice were fed control or HF diets, with or without 10% VV mixture for 8 weeks (n = 7 per group). The HF diet induced significant weight gain, adipose tissue accumulation, hepatic steatosis, and inflammation. The HF diet also significantly reduced hepatic ACO1, CPT1 mRNA expression, and α-diversity with distinct fecal microbiota profiles. On the other hand, VV mixture supplementation reduced serum TC, LDL-C levels and NAFLD scores. VV mixture supplementation also increased hepatic ACO1 and CPT1 mRNA expression, enhanced α-diversity, and enriched SCFA-producing bacteria, particularly the Lachnospiraceae NK4A136 group. In conclusion, the VV mixture attenuated HF diet-induced obesity, possibly through its high viscosity–mediated effects on hepatic fatty acid oxidation and gut microbiota modulation. Full article

Obesity and related metabolic disorders are major global health challenges. Postbiotics, such as heat-inactivated probiotics, have attracted attention for their improved safety, stability, and potential metabolic benefits compared to live probiotics. However, the comparative anti-obesity effects and mechanisms of live versus heat-inactivated Lactiplantibacillus plantarum FRT4 remain unclear, so this study systematically evaluated their effects and mechanisms in high-fat-diet-induced obese mice. Mice received oral administration of live or heat-inactivated FRT4 (prepared by heating in a water bath at 80 °C for 5 min) for 16 weeks. Comprehensive analyses included metabolic profiling, histological evaluation, serum and liver biomarkers, gut microbiota composition, liver metabolomics, and transcriptomics. Both live and inactivated FRT4 significantly reduced body weight gain, adiposity, hepatic steatosis, and dyslipidemia, with inactivated FRT4 exhibiting comparable or superior efficacy. Notably, inactivated FRT4 restored gut microbiota composition, increased short-chain fatty acid production, and regulated hepatic metabolic pathways. Multi-omics analyses revealed modulation of lipid biosynthesis, amino acid metabolism, and energy utilization pathways. Specifically, the “biosynthesis of unsaturated fatty acids” pathway was downregulated in metabolomics and significantly enriched in transcriptomics, highlighting its central role in FRT4M-mediated metabolic reprogramming. These findings demonstrate that heat-inactivated Lp. plantarum FRT4 exerts systemic anti-obesity effects via gut–liver axis modulation, supporting its potential as a promising postbiotic intervention for obesity and metabolic dysfunction. Full article

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is strongly associated with metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). IH exacerbates MASLD progression through oxidative stress, inflammation, and lipid accumulation. This study aims to investigate the impact of oxygen normalization on metabolic dysfunction in OSA patients using continuous positive airway pressure (CPAP) therapy, and in mice exposed to IH followed by a reoxygenation period. In the clinical study, 76 participants (44 OSA patients and 32 controls) were analyzed. OSA patients had higher insulin resistance, triglycerides, very low density lipoprotein (VLDL) content, and liver enzyme levels, along with a higher prevalence of liver steatosis. After 18 months of CPAP therapy, OSA patients showed significant improvements in insulin resistance, lipid profiles (total cholesterol and VLDL), liver function markers (AST and albumin), and steatosis risk scores (Fatty Liver Index and OWLiver test). In the experimental study, IH induced hepatic lipid accumulation, oxidative stress, and inflammation, and reoxygenation reversed these deleterious effects in mice. At the molecular level, IH downregulated fatty acid oxidation (FAO)-related genes, thus impairing the FAO process. Reoxygenation maintained elevated levels of lipogenic genes but restored FAO gene expression and activity, suggesting enhanced lipid clearance despite ongoing lipogenesis. Indeed, serum β hydroxybutyrate, a key marker of hepatic FAO in patients, was impaired in OSA patients but normalized after CPAP therapy, supporting improved FAO function. CPAP therapy improves lipid profiles, liver function, and MASLD progression in OSA patients. Experimental findings highlight the therapeutic potential of oxygen normalization in reversing IH-induced liver damage by FAO pathway restoration, indicating a metabolic reprogramming in the liver. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure. Capsaicin (CAP), the primary pungent compound in chili peppers, has previously been shown to prevent weight gain in high-fat diet (HFD)-induced obesity models. In this study, we investigated the potential of dietary CAP to prevent HFD-induced MASLD. Methods: C57BL/6 mice were fed an HFD (60% kcal from fat) with or without 0.01% CAP supplementation for 26 weeks. We evaluated CAP’s effects on hepatic fat accumulation, inflammation, and mitochondrial function to determine its role in preventing MASLD. Results: CAP acts as a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel. We confirmed TRPV1 expression in the liver and demonstrated that CAP activates hepatic TRPV1, thereby preventing steatosis, improving insulin sensitivity, reducing inflammation, and enhancing fatty acid oxidation. These beneficial effects were observed in wild-type but not in TRPV1 knockout mice. Mechanistically, CAP-induced TRPV1 activation promotes calcium influx and activates AMPK, which leads to SIRT1-dependent upregulation of PPARα and PGC-1α, enhancing mitochondrial biogenesis and lipid metabolism. Conclusions: Our findings suggest that dietary CAP prevents MASLD through TRPV1 activation. TRPV1 signaling represents a promising therapeutic target for the prevention and management of MASLD in individuals with metabolic disorders. Full article

Perturbations in the tightly regulated processes of VLDL biosynthesis and secretion can directly impact both liver and cardiovascular health. Patients with metabolic disorders have an increased risk of developing hepatic steatosis, which can lead to cirrhosis. These associated metabolic risks underscore the importance of discerning the role of different cellular proteins involved in VLDL biogenesis, transport, and secretion. Small VCP-Interacting Protein (SVIP) has been identified as a component of VLDL transport vesicles and VLDL secretion. This study evaluates the cellular effects stemming from the CRISPR-Cas9-mediated depletion of SVIP in rat hepatocytes. The SVIP-knockout (KO) cells display an increased VLDL retention with elevated intracellular levels of ApoB100 and neutral lipid staining. RNA sequencing studies reveal an impaired PPARα and Nrf2 signaling in the SVIP KO cells, implying a state of metabolic reprograming, with a shift from fatty acid uptake, synthesis, and oxidation to cells favoring the activation of glucose by impaired glycogen storage and increased glucose release. Additionally, SVIP KO cells exhibit a transcriptional profile indicative of acute phase response (APR) in hepatocytes. Many inflammatory markers and genes associated with APR are upregulated in the SVIP KO hepatocytes. In accordance with an APR-like response, the cells also demonstrate an increase in mRNA expression of genes associated with protein synthesis. Together, our data demonstrate that SVIP is critical in maintaining hepatic lipid homeostasis and metabolic balance by regulating key pathways such as PPARα, Nrf2, and APR. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health challenge characterized by complex adipose–liver interactions mediated by adipokines and hepatokines. Despite rapid field evolution, a comprehensive understanding of research trends and translational advances remains fragmented. This study systematically maps the scientific landscape through bibliometric analysis, identifying emerging domains and future clinical translation directions. Methods: A comprehensive bibliometric analysis of 1002 publications from 2004 to 2025 was performed using thematic mapping, temporal trend evaluation, and network analysis. Analysis included geographical and institutional distributions, thematic cluster identification, and research paradigm evolution assessment, focusing specifically on adipokine–hepatokine signaling mechanisms and clinical implications. Results: The United States and China are at the forefront of research output, whereas European institutions significantly contribute to mechanistic discoveries. The thematic map analysis reveals the motor/basic themes residing at the heart of the field, such as insulin resistance, fatty liver, metabolic syndrome, steatosis, fetuin-A, and other related factors that drive innovation. Basic clusters include metabolic foundations (obesity, adipose tissue, FGF21) and adipokine-centered subjects (adiponectin, leptin, NASH). New themes focus on inflammation, oxidative stress, gut microbiota, lipid metabolism, and hepatic stellate cells. Niche areas show targeted fronts such as exercise therapies, pediatric/novel adipokines (chemerin, vaspin, omentin-1), and advanced molecular processes that focus on AMPK and endoplasmic-reticulum stress. Temporal analysis shows a shift from single liver studies to whole models that include the gut microbiota, mitochondrial dysfunction, and interactions between other metabolic systems. The network analysis identifies nine major clusters: cardiovascular–metabolic links, adipokine–inflammatory pathways, hepatokine control, and new therapeutic domains such as microbiome interventions and cellular stress responses. Conclusions: In summary, this study delineates current trends and emerging areas within the field and elucidates connections between mechanistic research and clinical translation to provide guidance for future research and development in this rapidly evolving area. Full article

Huntington’s disease (HD) is characterized by progressive neurodegeneration, but increasing evidence points to multisystemic involvement, including early hepatic steatosis in pediatric HD. Therefore, it is important to consider systemic alterations, particularly in liver lipid metabolism. In this study, we analyzed fatty acid (FA) profiles in two symptomatic HD mouse models: 2-month-old R6/2 mice representing early-onset HD and 22-month-old Hdh^Q150/Q150 (Hdh) mice representing late-onset HD, along with age-matched wild-type (WT) controls. FA composition in liver tissue was assessed by gas chromatography–mass spectrometry (GC–MS). In R6/2 mice, we observed increased levels of total iso-branched chain, monounsaturated, and n-6 polyunsaturated FAs compared to WT. In contrast, only a few FA species showed reduced concentrations in Hdh mice. Overall, our results indicate that R6/2 mice exhibit more pronounced alterations in hepatic FA profiles than Hdh mice, suggesting that early-onset HD may be associated with more severe peripheral metabolic dysregulation. Full article

The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, like its homologue Nrf2, further responds to oxidative stress by binding with small Maf proteins (sMaf) to the promotor antioxidant response element (ARE). Given these facts, investigating the crosstalk between Nrf1 and HCV was a logical next step. In HCV-replicating cells, we observed reduced levels of Nrf1. Furthermore, activation of Nrf1-dependent target genes is impaired due to sMaf sequestration in replicase complexes. This results in a shortage of sMaf proteins in the nucleus, trapping Nrf1 at the replicase complexes and further limiting its function. Weakened Nrf1 activity contributes to impaired cholesterol removal, which occurs alongside an elevated intracellular cholesterol level and inhibited LXRα promoter activation. Furthermore, inhibition of Nrf1 activity correlated with a kinome profile characteristic of steatosis and enhanced inflammation—factors contributing to HCV pathogenesis. Our results indicate that activation of Nrf1-dependent target genes is impaired in HCV-positive cells. This, in turn, favours viral morphogenesis, as evidenced by enhanced replication and increased production of viral progeny. Full article

There are currently no approved therapeutic treatments targeting metabolic dysfunction-associated steatotic liver disease (MASLD). Albumin, a liver-produced plasma protein with anti-inflammatory and antioxidant properties, is reduced in advanced liver disease. Considering the role of chronic obesity-induced inflammation in MASLD pathogenesis, we investigated whether albumin administration could prevent disease progression to metabolic dysfunction-associated steatohepatitis (MASH). MASLD was induced in mice using a high-fat and high-cholesterol (PC) treatment for 8 weeks, followed by treatment with bovine serum albumin (BSA; 0.8 mg/kg) every three days for another 8 weeks. This regimen prevented time-dependent weight gain, regardless of diet, with 57% and 27% reductions in mice fed a standard chow (Std Chow) or PC diet, respectively. Further, supplementation reduced nuclear factor kappa B (NF-κB) activation by 2.8-fold (p = 0.0328) in PC-fed mice, consistent with albumin’s known anti-inflammatory properties. Unexpectedly, albumin also reduced hepatic neutral lipid accumulation and circulating non-esterified fatty acids. While PC-fed mice did not exhibit full progression to MASH, albumin treatment significantly increased hepatic matrix metalloproteinase-2 expression, suggesting the inhibition of early fibrotic signalling. While further studies are needed to elucidate the underlying mechanisms, these findings offer new insight into the potential of albumin, either alone or in combination with other therapies, to reduce hepatic steatosis in MASLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of liver conditions, from simple hepatic steatosis to its more severe inflammatory form known as metabolic dysfunction-associated steatohepatitis (MASH). Despite its growing clinical significance and association with cirrhosis and cancer, there are currently few pharmacological treatments available for MASLD, highlighting the urgent need for new therapeutic strategies. This narrative review aims to elucidate the molecular mechanisms of lipophagy in MASLD progression, emphasizing how its dysfunction contributes to hepatic steatosis and lipotoxicity. We also explore the intersection of lipophagy failure with oxidative stress and inflammation in the liver, focusing on key signaling pathways, such as mTORC1 and AMPK, and discuss the therapeutic potential of targeting these pathways by systematically reviewing the literature from PubMed, Scopus, and Google Scholar databases. Recent studies suggest that lipophagy, the selective autophagic degradation of lipid droplets, is crucial for maintaining hepatic lipid homeostasis. Indeed, some vital components of the lipophagy machinery seem to be functionally inhibited in MASLD, resulting in the accumulation of intracellular triacylglycerol (TAG), lipotoxicity, and subsequent oxidative stress, all of which contribute to disease progression. In summary, impaired lipophagy is a central pathological mechanism in MASLD, making it an important therapeutic target. A deeper understanding of these mechanisms may offer new strategic insights for combating the progression of MASLD/MASH. Full article