RÉSUMÉ
In this editorial, we comment on three articles published in a recent issue of World Journal of Gastroenterology. There is a pressing need for new research on autophagy's role in gastrointestinal (GI) disorders, and also novel insights into some liver conditions, such as metabolic dysfunction-associated fatty liver disease (MAFLD) and acute liver failure (ALF). Despite advancements, understanding autophagy's intricate mechanisms and implications in these diseases remains incomplete. Moreover, MAFLD's pathogenesis, encompassing hepatic steatosis and metabolic dysregulation, require further elucidation. Similarly, the mechanisms underlying ALF, a severe hepatic dysfunction, are poorly understood. Innovative studies exploring the interplay between autophagy and GI disorders, as well as defined mechanisms of MAFLD and ALF, are crucial for identifying therapeutic targets and enhancing diagnostic and treatment strategies to mitigate the global burden of these diseases.
Sujet(s)
Autophagie , Défaillance hépatique aigüe , Humains , Défaillance hépatique aigüe/métabolisme , Défaillance hépatique aigüe/anatomopathologie , Défaillance hépatique aigüe/étiologie , Foie/anatomopathologie , Foie/métabolisme , Animaux , Stéatose hépatique non alcoolique/métabolisme , Stéatose hépatique non alcoolique/anatomopathologie , Maladies gastro-intestinales/métabolisme , Maladies gastro-intestinales/anatomopathologie , Maladies gastro-intestinales/étiologie , Stéatose hépatique/métabolisme , Stéatose hépatique/anatomopathologieRÉSUMÉ
Choline is recognized as an essential nutrient for Atlantic salmon at all developmental stages. However, its dietary requirement is not well defined. Choline plays a critical role in lipid transport, and the clearest deficiency sign is intestinal steatosis. The present work, aiming to find whether lipid source and fish size may affect steatosis symptoms, was one of a series of studies conducted to identify which production-related conditions may influence choline requirement. Six choline-deficient diets were formulated varying in ratios of rapeseed oil to fish oil and fed to Atlantic salmon of 1.5 and 4.5 kg. After eight weeks, somatic characteristics were observed, and the severity of intestinal steatosis was assessed by histological, biochemical, and molecular analyses. Fatty acid composition in pyloric intestine, mesenteric tissue, and liver samples was also quantified. The increasing rapeseed oil level increased lipid digestibility markedly, enhancing lipid supply to the fish. Moreover, small fish consumed more feed, and consequently had a higher lipid intake. In conclusion, the results showed that choline requirement depends on dietary lipid load, which depends on the fatty acid profile as well as the fish size.
Sujet(s)
Aliment pour animaux , Huiles de poisson , Huile de colza , Salmo salar , Animaux , Huile de colza/administration et posologie , Salmo salar/métabolisme , Salmo salar/croissance et développement , Huiles de poisson/administration et posologie , Aliment pour animaux/analyse , Acides gras/métabolisme , Acides gras/analyse , Maladies des poissons/anatomopathologie , Maladies des poissons/métabolisme , Stéatose hépatique/médecine vétérinaire , Stéatose hépatique/métabolisme , Stéatose hépatique/étiologie , Stéatose hépatique/anatomopathologie , Choline/métabolisme , Choline/administration et posologie , Régime alimentaire/médecine vétérinaire , Foie/métabolisme , Foie/anatomopathologieRÉSUMÉ
In consideration of several serious side effects induced by the classical AF-2 involved "lock" mechanism, recently disclosed PPARγ-Ser273 phosphorylation mode of action has become an alternative and mainstream mechanism for currently PPARγ-based drug discovery and development with an improved therapeutic index. In this study, by virtue of structure-based virtual high throughput screening (SB-VHTS), structurally chemical optimization by targeting the inhibition of the PPARγ-Ser273 phosphorylation as well as in vitro biological evaluation, which led to the final identification of a chrysin-based potential hit (YGT-31) as a novel selective PPARγ modulator with potent binding affinity and partial agonism. Further in vivo evaluation demonstrated that YGT-31 possessed potent glucose-lowering and relieved hepatic steatosis effects without involving the TZD-associated side effects. Mechanistically, YGT-31 presented such desired therapeutic index, mainly because it effectively inhibited the CDK5-mediated PPARγ-Ser273 phosphorylation, selectively elevated the level of insulin sensitivity-related Glut4 and adiponectin but decreased the expression of insulin-resistance-associated genes PTP1B and SOCS3 as well as inflammation-linked genes IL-6, IL-1ß and TNFα. Finally, the molecular docking study was also conducted to uncover an interesting hydrogen-bonding network of YGT-31 with PPARγ-Ser273 phosphorylation-related key residues Ser342 and Glu343, which not only gave a clear verification for our targeting modification but also provided a proof of concept for the abovementioned molecular mechanism.
Sujet(s)
Stéatose hépatique , Flavonoïdes , Récepteur PPAR gamma , Récepteur PPAR gamma/métabolisme , Récepteur PPAR gamma/agonistes , Flavonoïdes/pharmacologie , Flavonoïdes/composition chimique , Flavonoïdes/synthèse chimique , Relation structure-activité , Stéatose hépatique/traitement médicamenteux , Stéatose hépatique/métabolisme , Humains , Structure moléculaire , Diabète de type 2/traitement médicamenteux , Animaux , Hypoglycémiants/pharmacologie , Hypoglycémiants/composition chimique , Hypoglycémiants/synthèse chimique , Simulation de docking moléculaire , Relation dose-effet des médicaments , Souris , Mâle , Évaluation préclinique de médicamentRÉSUMÉ
OBJECTIVE: The association of appendicular skeletal muscle mass (ASM), grip strength and fat-to-muscle ratio (FMR) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) are not well known. MATERIALS AND METHODS: This study included participants older than 40 years who underwent bioelectrical impedance assessment in Prevalence of Metabolic Diseases and Risk Factors in Shunde (SPEED-Shunde). We measured grip strength with an electronic grip strength metre. ASM and grip strength were adjusted by dividing body mass index (BMI). FMR was calculated as total fat mass to total muscle mass. Liver steatosis and liver fibrosis were evaluated by vibration-controlled transient elastography. Multifactorial logistic regression was used to analyse the relationship between ASM, grip strength, FMR, and MASLD or MASLD-associated liver fibrosis. We performed subgroup analyses according to sex, age and BMI. Interaction tests and linear trend tests were also conducted. RESULTS: This study included a total of 3277 participants. FMR was positively associated with MASLD (OR: 1.89, 95% CI: 1.66-2.15) and MASLD-associated liver fibrosis (OR: 1.70, 95% CI: 1.22-2.37). While ASM/BMI (OR: 0.59, 95% CI: 0.52-0.67) or grip strength/BMI (OR: 0.72, 95% CI: 0.66-0.78) were negatively associated with MASLD. Interactions were observed between ASM/BMI and age, grip strength and sex in MASLD, as well as FMR and MASLD-associated liver fibrosis. CONCLUSION: In a middle-to-elderly aged population, FMR was positively associated with the risk of MASLD and MASLD-associated liver fibrosis, and muscle mass and grip strength were negatively associated with MASLD, rather than MASLD-associated liver fibrosis.
Sujet(s)
Indice de masse corporelle , Force de la main , Muscles squelettiques , Humains , Mâle , Force de la main/physiologie , Femelle , Adulte d'âge moyen , Muscles squelettiques/physiopathologie , Muscles squelettiques/imagerie diagnostique , Sujet âgé , Stéatose hépatique/physiopathologie , Stéatose hépatique/épidémiologie , Stéatose hépatique/complications , Facteurs de risque , Cirrhose du foie/physiopathologie , Cirrhose du foie/complications , Cirrhose du foie/épidémiologie , Études transversales , Imagerie d'élasticité tissulaire , Adulte , Impédance électrique , Tissu adipeux/imagerie diagnostique , Composition corporelleRÉSUMÉ
Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.
Sujet(s)
Alimentation riche en graisse , Fructose , Protéine-1 de type kelch associée à ECH , Facteur-2 apparenté à NF-E2 , Caractères sexuels , Transduction du signal , Animaux , Facteur-2 apparenté à NF-E2/métabolisme , Femelle , Mâle , Alimentation riche en graisse/effets indésirables , Transduction du signal/effets des médicaments et des substances chimiques , Rats , Protéine-1 de type kelch associée à ECH/métabolisme , Autophagie/effets des médicaments et des substances chimiques , Protéine-1 liant la boite X/métabolisme , Protéine-1 liant la boite X/génétique , Modèles animaux de maladie humaine , Stéatose hépatique/métabolisme , Stéatose hépatique/anatomopathologie , Foie/métabolisme , Foie/anatomopathologie , Foie/effets des médicaments et des substances chimiques , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Rat Wistar , Stress oxydatif/effets des médicaments et des substances chimiques , Protéines associées aux microtubulesRÉSUMÉ
Hepatocyte organoids (HOs) have superior hepatic functions to cholangiocyte-derived organoids but suffer from shorter lifespans. To counteract this, we co-cultured pig HOs with adipose-derived mesenchymal stem cells (A-MSCs) and performed transcriptome analysis. The results revealed that A-MSCs enhanced the collagen synthesis pathways, which are crucial for maintaining the three-dimensional structure and extracellular matrix synthesis of the organoids. A-MSCs also increased the expression of liver progenitor cell markers (KRT7, SPP1, LGR5+, and TERT). To explore HOs as a liver disease model, we exposed them to alcohol to create an alcoholic liver injury (ALI) model. The co-culture of HOs with A-MSCs inhibited the apoptosis of hepatocytes and reduced lipid accumulation of HOs. Furthermore, varying ethanol concentrations (0-400 mM) and single-versus-daily exposure to HOs showed that daily exposure significantly increased the level of PLIN2, a lipid storage marker, while decreasing CYP2E1 and increasing CYP1A2 levels, suggesting that CYP1A2 may play a critical role in alcohol detoxification during short-term exposure. Moreover, daily alcohol exposure led to excessive lipid accumulation and nuclear fragmentation in HOs cultured alone. These findings indicate that HOs mimic in vivo liver regeneration, establishing them as a valuable model for studying liver diseases, such as ALI.
Sujet(s)
Apoptose , Techniques de coculture , Hépatocytes , Régénération hépatique , Cellules souches mésenchymateuses , Organoïdes , Cellules souches mésenchymateuses/métabolisme , Animaux , Hépatocytes/métabolisme , Hépatocytes/anatomopathologie , Organoïdes/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Suidae , Tissu adipeux/cytologie , Tissu adipeux/métabolisme , Éthanol , Stéatose hépatique/anatomopathologie , Stéatose hépatique/métabolisme , Maladies alcooliques du foie/anatomopathologie , Maladies alcooliques du foie/métabolisme , Métabolisme lipidiqueRÉSUMÉ
Physical activity is a cornerstone of a healthy lifestyle, with benefits in managing chronic diseases. This study investigates the relationship between physical activity and liver-related outcomes with or without steatotic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD and increased alcohol intake (MetALD). The primary outcomes of interest were overall survival in the entire population, individuals without steatotic liver disease, patients with MASLD, and those with MetALD. The secondary outcomes included the incidence of liver cirrhosis. Participants were categorized based on physical activity frequency and Kaplan-Meier survival curves and Cox proportional hazards models were used for analysis. Higher physical activity was associated with significantly better survival in the overall cohort and MASLD cohort before and after inverse probability of treatment weighting (IPTW). In participants without steatotic liver disease and the MetALD cohort, higher physical activity showed significant survival improvement after IPTW. For the incidence of liver cirrhosis, higher physical activity showed significant associations before IPTW in the overall cohort and MASLD cohort, but these associations were not significant after IPTW. Marginal significance was observed in the MetALD cohort before and after IPTW. In conclusion. promoting physical activity may be key in improving liver-related outcomes.
Sujet(s)
Exercice physique , Stéatose hépatique , Cirrhose du foie , Humains , Mâle , Femelle , Adulte d'âge moyen , Cirrhose du foie/mortalité , Cirrhose du foie/complications , Incidence , Stéatose hépatique/mortalité , Stéatose hépatique/thérapie , Stéatose hépatique/épidémiologie , Stéatose hépatique/complications , Études de cohortes , Adulte , Sujet âgé , Modèles des risques proportionnels , Estimation de Kaplan-MeierRÉSUMÉ
Progression of metabolic dysfunction-associated steatites liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis, and MASH can lead to cirrhosis and hepatocellular carcinoma. Previously, we showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2-related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASH-linked liver fibrosis and tumorigenesis. Male and female mice with flox alleles for genes encoding Nrf1 (Nfe2l1), Nrf2 (Nfe2l2), or both were fed a MASH-inducing diet enriched with high fat, fructose, and cholesterol (HFFC) or a control diet for 24-52 weeks. During this period, hepatocyte Nrf1, Nrf2, or combined deficiency for ~7 days, ~7 weeks, and ~35 weeks was induced by administering mice hepatocyte-targeting adeno-associated virus (AAV) expressing Cre recombinase. The effects on MASH, markers of liver fibrosis and proliferation, and liver tumorigenesis were compared to control mice receiving AAV-expressing green fluorescent protein. Also, to assess the impact of Nrf1 and Nrf2 induction on liver fibrosis, HFFC diet-fed C57bl/6J mice received weekly injections of carbon tetrachloride, and from week 16 to 24, mice were treated with the Nrf2-activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and these groups were compared to control. Compared to the control diet, 24-week feeding with the HFFC diet increased bodyweight as well as liver weight, steatosis, and inflammation. It also increased hepatocyte proliferation and a marker of liver damage, p62. Hepatocyte Nrf1 and combined deficiency increased liver steatosis in control diet-fed but not HFFC diet-fed mice, and increased liver inflammation under both diet conditions. Hepatocyte Nrf1 deficiency also increased hepatocyte proliferation, whereas combined deficiency did not, and this also occurred for p62 level in control diet-fed conditions. In 52-week HFFC diet-fed mice, 35 weeks of hepatocyte Nrf1 deficiency, but not combined deficiency, resulted in more liver tumors in male mice, but not in female mice. In contrast, hepatocyte Nrf2 deficiency had no effect on any of these parameters. However, in the 15-week CCL4-exposed and 24-week HFFC diet-fed mice, Nrf2 induction with bardoxolone reduced liver steatosis, inflammation, fibrosis, and proliferation. Induction of hepatic Nrf1 activity with hNRF1 enhanced the effect of bardoxolone on steatosis and may have stimulated liver progenitor cells. Physiologic Nrf1 delays MASLD progression, Nrf2 induction alleviates MASH, and combined enhancement synergistically protects against steatosis and may facilitate liver repair.
Sujet(s)
Hépatocytes , Facteur-2 apparenté à NF-E2 , Animaux , Facteur-2 apparenté à NF-E2/métabolisme , Facteur-2 apparenté à NF-E2/génétique , Souris , Hépatocytes/métabolisme , Mâle , Femelle , Évolution de la maladie , Souris de lignée C57BL , Stéatose hépatique/métabolisme , Stéatose hépatique/anatomopathologie , Stéatose hépatique/génétique , Cirrhose du foie/métabolisme , Cirrhose du foie/anatomopathologie , Cirrhose du foie/génétique , Tumeurs du foie/métabolisme , Tumeurs du foie/génétique , Tumeurs du foie/anatomopathologie , Facteur-1 apparenté à NF-E2/métabolisme , Facteur-1 apparenté à NF-E2/génétique , Facteur nucléaire-1 respiratoire/métabolisme , Facteur nucléaire-1 respiratoire/génétique , Alimentation riche en graisse/effets indésirables , Foie/métabolisme , Foie/anatomopathologie , HumainsRÉSUMÉ
Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.
Sujet(s)
Souris de lignée C57BL , Obésité , Lymphocytes T , Animaux , Obésité/immunologie , Obésité/complications , Obésité/étiologie , Femelle , Mâle , Souris , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Alimentation riche en graisse/effets indésirables , Facteurs sexuels , Rate/immunologie , Rate/anatomopathologie , Caractères sexuels , Cellules myéloïdes suppressives/immunologie , Cellules myéloïdes suppressives/métabolisme , Stéatose hépatique/étiologie , Stéatose hépatique/immunologie , Stéatose hépatique/anatomopathologie , Inflammation/immunologie , Inflammation/anatomopathologie , Inflammation/étiologieRÉSUMÉ
The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established.
Sujet(s)
Carcinome hépatocellulaire , Alimentation riche en graisse , Modèles animaux de maladie humaine , Tumeurs du foie , Animaux , Carcinome hépatocellulaire/métabolisme , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/génétique , Mâle , Tumeurs du foie/métabolisme , Tumeurs du foie/anatomopathologie , Tumeurs du foie/génétique , Souris , Alimentation riche en graisse/effets indésirables , Souris de lignée C57BL , Humains , Foie/métabolisme , Foie/anatomopathologie , Stéatose hépatique/métabolisme , Stéatose hépatique/anatomopathologie , Streptozocine , Cirrhose du foie/métabolisme , Cirrhose du foie/anatomopathologie , Transcriptome , Obésité/métabolisme , Obésité/complications , Diabète de type 2/complications , Diabète de type 2/métabolisme , Stéatose hépatique non alcoolique/métabolisme , Stéatose hépatique non alcoolique/anatomopathologie , Stéatose hépatique non alcoolique/complicationsRÉSUMÉ
BACKGROUND: Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. OBJECTIVE: To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. METHOD: In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. RESULTS: Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. CONCLUSION: These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043).
Sujet(s)
Microbiome gastro-intestinal , Foie , Silymarine , Humains , Silymarine/pharmacologie , Silymarine/usage thérapeutique , Silymarine/administration et posologie , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Mâle , Femelle , Adulte d'âge moyen , Méthode en double aveugle , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Foie/anatomopathologie , Adulte , Stéatose hépatique/traitement médicamenteux , Compléments alimentaires , ARN ribosomique 16S/génétique , Imagerie d'élasticité tissulaire , Sujet âgéRÉSUMÉ
Macrophages show high plasticity and play a vital role in the progression of metabolic dysfunction-associated steatohepatitis (MASH). X-box binding protein 1 (XBP1), a key sensor of the unfolded protein response, can modulate macrophage-mediated pro-inflammatory responses in the pathogenesis of MASH. However, how XBP1 influences macrophage plasticity and promotes MASH progression remains unclear. Herein, we formulated an Xbp1 siRNA delivery system based on folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles (FT@XBP1) to explore the precise role of macrophage-specific Xbp1 deficiency in the progression of MASH. FT@XBP1 was specifically internalized into hepatic macrophages and subsequently inhibited the expression of spliced XBP1 both in vitro and in vivo. It promoted M1-phenotype macrophage repolarization to M2 macrophages, reduced the release of pro-inflammatory factors, and alleviated hepatic steatosis, liver injury, and fibrosis in mice with fat-, fructose- and cholesterol-rich diet-induced MASH. Mechanistically, FT@XBP1 promoted macrophage polarization toward the M2 phenotype and enhanced the release of exosomes that could inhibit the activation of hepatic stellate cells. A promising macrophage-targeted siRNA delivery system was revealed to pave a promising strategy in the treatment of MASH.
Sujet(s)
Acide folique , Macrophages , Petit ARN interférent , Protéine-1 liant la boite X , Animaux , Mâle , Souris , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Stéatose hépatique/métabolisme , Acide folique/composition chimique , Macrophages/métabolisme , Macrophages/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Nanoparticules/composition chimique , Protéine-1 liant la boite X/métabolismeRÉSUMÉ
BACKGROUND/AIMS: Pancreatic steatosis (PS) is a pathology associated with metabolic syndrome (MS), endocrin and exocrine disfunctions of the pancreas, and fatty liver. The data on the frequency of PS are very limited. We aimed to evaluate the frequency of PS detected by transabdominal ultrasonography (TAU) in gastroenterology clinics located in different geographical regions of Turkey and the factors associated with it. MATERIALS AND METHODS: Volunteers were evaluated by TAU for PS and hepatosteatosis (HS), and its degree. Pancreatic stiffness was evaluated by ultrasonographic shear wave elastography (SWE). All demographic, physical, and biochemical parametres were measured. RESULTS: A total of 1700 volunteers from 14 centers throughout Turkey were included in the study. Mean age was 48.03 ± 20.86 years (56.9% female). Prevalance of PS was detected in 68.9%. In the PS group, age, body mass index (BMI), waist circumference, systolic blood pressure, fasting blood glucose (FBG), lipid levels, insulin resistance, diabetes mellitus, hypertension, MS frequency, and pancreatic SWE score were increasing, and fecal elastase level was decreasing in correlation with the degree of PS. The frequency of HS was 55.5%. Hepatosteatosis [odds ratio (OR): 9.472], increased age (OR: 1.02), and BMI (OR: 1.089) were independent risk factors for the occurrence of PS. Lean-PS rate was 11.8%. The lean-PS group was predominantly female and younger than non-lean PS. Also it has lower blood pressure, FBG, liver enzymes, lipid levels, and HS rates. CONCLUSION: The frequency of PS was found 68.9% in Turkey. Its relationship was determined with age, BMI, HS, MS (and its components), pancreatic stiffness, and fecal elastase level.
Sujet(s)
Imagerie d'élasticité tissulaire , Stéatose hépatique , Syndrome métabolique X , Maladies du pancréas , Humains , Turquie/épidémiologie , Femelle , Adulte d'âge moyen , Mâle , Prévalence , Adulte , Facteurs de risque , Syndrome métabolique X/épidémiologie , Maladies du pancréas/épidémiologie , Stéatose hépatique/épidémiologie , Indice de masse corporelle , Sujet âgé , Pancréas/imagerie diagnostique , Pancreatic elastase/analyse , Tour de taille , Insulinorésistance , Glycémie/analyse , Glycémie/métabolismeRÉSUMÉ
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has surged due to changes in economic and lifestyle patterns, leading to significant health challenges. Previous reports have studied the establishment of animal and cellular models for MASLD, highlighting differences between them. In this study, a cellular model was created by inducing fat accumulation in MASLD. HepG2 cells were stimulated with the unsaturated fatty acid oleic acid at various concentrations (0.125 mM, 0.25 mM, 0.5 mM, 1 mM) to emulate MASLD. The model's efficacy was assessed using cell counting kit-8 assays, Oil Red O staining, and lipid content analysis. This study aimed to create a simple-to-operate cellular model for MASLD cells. Results from the cell counting kit-8 assays showed that the survival of HepG2 cells was dependent on the concentration of oleic acid, with a GI50 of 1.875 mM. Cell viability in the 0.5 mM and 1 mM groups were significantly lower than those in the control group (P < 0.05). Furthermore, Oil Red O staining and lipid content analysis examined fat deposition at varying oleic acid concentrations (0.125 mM, 0.25 mM, 0.5 mM, 1 mM) on HepG2 cells. The lipid content of the 0.25 mM, 0.5 mM, and 1 mM groups was significantly higher than that of the control group (P < 0.05). Additionally, triglyceride levels in the OA groups were significantly higher than those in the control group (P < 0.05).
Sujet(s)
Stéatose hépatique , Acide oléique , Humains , Cellules HepG2 , Acide oléique/pharmacologie , Stéatose hépatique/métabolisme , Stéatose hépatique/anatomopathologie , Composés azoïques , Métabolisme lipidique/physiologie , Modèles biologiquesRÉSUMÉ
Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.
Sujet(s)
Prédisposition génétique à une maladie , Étude d'association pangénomique , Foie , Humains , Femelle , Mâle , Facteurs de risque , Prédisposition génétique à une maladie/génétique , Foie/imagerie diagnostique , Foie/métabolisme , Foie/anatomopathologie , Adulte d'âge moyen , Polymorphisme de nucléotide simple/génétique , Imagerie par résonance magnétique , Stéatose hépatique non alcoolique/génétique , Stéatose hépatique non alcoolique/imagerie diagnostique , Adulte , Sujet âgé , Stéatose hépatique/génétique , Stéatose hépatique/imagerie diagnostiqueRÉSUMÉ
BACKGROUND: With the fast pace of modern life, people have less time for meals, but few studies have examined the association between the habit of fast eating and metabolic diseases. OBJECTIVE: Combining the results of the current study and the prior ones, we aimed to investigate the possible relationship between fast eating and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: This is a sub-analysis of a multicenter cross-sectional study of 1965 participants investigated the association between fast eating and MASLD in Chinese. Fast eating was defined as meal time less than five minutes and participants were divided into three categories based on their self-reported frequency of fast eating: ≤1 time/month, ≤1 time/week and ≥2 times/week. We further conducted a literature search for available studies published before November, 2023 as well as a meta-analysis to investigate the association between fast eating and MASLD. RESULTS: The proportion of MASLD was 59.3%, 50.5%, and 46.2% in participants with fast eating ≥2 times/week, ≤1 time/week and ≤1 time/month, respectively (P for trend <0.001). The frequency of fast eating was independently associated with risk of MASLD after multiple adjustment for sex, age, demographics, smoking and drinking status, BMI and clinical metabolic parameters (OR, 1.29; 95%CI, 1.09-1.53). Participants who ate fast frequently (≥2 times/week) had 81% higher risk of MASLD (P = 0.011). A meta-analysis of five eligible studies confirmed that frequent fast eating was associated with increased risk of MASLD (pooled OR, 1.22; 95%CI, 1.07-1.39). CONCLUSIONS: Frequent fast eating was associated with an increased risk of MASLD.
Sujet(s)
Comportement alimentaire , Humains , Études transversales , Mâle , Femelle , Adulte d'âge moyen , Adulte , Facteurs de risque , Facteurs temps , Chine/épidémiologie , Maladies métaboliques/épidémiologie , Maladies métaboliques/étiologie , Repas , Stéatose hépatique/épidémiologieRÉSUMÉ
Metabolic-associated steatohepatitis (MASH) and ulcerative colitis (UC) exhibit a complex interconnection with immune dysfunction, dysbiosis of the gut microbiota, and activation of inflammatory pathways. This study aims to identify and validate critical butyrate metabolism-related shared genes between both UC and MASH. Clinical information and gene expression profiles were sourced from the Gene Expression Omnibus (GEO) database. Shared butyrate metabolism-related differentially expressed genes (sBM-DEGs) between UC and MASH were identified via various bioinformatics methods. Functional enrichment analysis was performed, and UC patients were categorized into subtypes using the consensus clustering algorithm based on sBM-DEGs. Key genes within sBM-DEGs were screened through Random Forest, Support Vector Machines-Recursive Feature Elimination, and Light Gradient Boosting. The diagnostic efficacy of these genes was evaluated using receiver operating characteristic (ROC) analysis on independent datasets. Additionally, the expression levels of characteristic genes were validated across multiple independent datasets and human specimens. Forty-nine shared DEGs between UC and MASH were identified, with enrichment analysis highlighting significant involvement in immune, inflammatory, and metabolic pathways. The intersection of butyrate metabolism-related genes with these DEGs produced 10 sBM-DEGs. These genes facilitated the identification of molecular subtypes of UC patients using an unsupervised clustering approach. ANXA5, CD44, and SLC16A1 were pinpointed as hub genes through machine learning algorithms and feature importance rankings. ROC analysis confirmed their diagnostic efficacy in UC and MASH across various datasets. Additionally, the expression levels of these three hub genes showed significant correlations with immune cells. These findings were validated across independent datasets and human specimens, corroborating the bioinformatics analysis results. Integrated bioinformatics identified three significant biomarkers, ANXA5, CD44, and SLC16A1, as DEGs linked to butyrate metabolism. These findings offer new insights into the role of butyrate metabolism in the pathogenesis of UC and MASH, suggesting its potential as a valuable diagnostic biomarker.