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INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a healthcare issue of growing concern. Its development is multifactorial, and it is more commonly seen in obese patients. In those circumstances, intracellular lipid overload ensues, resulting in oxidative stress that might be responsible for progression toward steatohepatitis. Novel therapeutic approaches that are effective in weight management are expected to improve the course of MASLD. One of the potential mechanisms involved in such protective properties may relate to the reduction in oxidative stress. MATERIAL AND METHODS: The induction of steatosis and the assessment of oxidative stress level and expression of antioxidant enzymes (superoxide dismutase - SOD, glutathione peroxidase - GPx and catalase - Cat) in HepG2 hepatoma cell line subjected to glucagon and exenatide treatment. RESULTS: Exenatide monotherapy successfully reduced lipid accumulation by 25%. Significant reductions in markers of oxidative stress (reactive oxygen species and malondialdehyde) were obtained in cells subjected to combined treatment with glucagon and exenatide (by 24 and 21%, respectively). Reduced burden of oxidative stress was associated with elevated expression of SOD and GPx but not Cat. CONCLUSIONS: Combined activation of glucagon-like peptide-1 (GLP-1) and glucagon receptors reduces oxidative stress in HepG2 steatotic cell cultures. This observation may stem from increased antioxidative potential.
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Catalasa , Exenatida , Glucagón , Glutatión Peroxidasa , Estrés Oxidativo , Superóxido Dismutasa , Humanos , Exenatida/farmacología , Estrés Oxidativo/efectos de los fármacos , Células Hep G2 , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Catalasa/metabolismo , Glucagón/metabolismo , Glucagón/farmacología , Superóxido Dismutasa/metabolismo , Antioxidantes/farmacología , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Ponzoñas/farmacología , Péptidos/farmacología , Hipoglucemiantes/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Background: Fatty liver index (FLI) and hepatic steatosis index (HSI) are serologic scores used to detect liver steatosis. However, their diagnostic performance in people with HIV (PWH) remains unclear. We performed an external validation of FLI and HSI in the Swiss HIV Cohort Study. Methods: We systematically performed vibration-controlled transient elastography (VCTE) among Swiss HIV Cohort Study participants at Bern University Hospital between November 2019 and August 2021. Individuals with viral hepatitis and pregnant women were excluded. We defined liver steatosis as controlled attenuation parameter ≥248 dB/m using VCTE. Model discrimination was assessed with the C-index and model calibration with calibration plots. A decision curve analysis was performed to compare the clinical usefulness of both scores. Results: Of 321 participants, 91 (28.4%) were female, the median age was 51.4 years (IQR, 42-59), 230 (71.7%) were Caucasian, and 164 (51.1%) had a body mass index >25 kg/m2. VCTE-confirmed liver steatosis was present in 158 (49.2%). Overall, 125 (38.9%) had an FLI ≥60, and 128 (39.9%) had an HSI ≥36. At these cutoffs, the C-index to diagnose liver steatosis was 0.85 for FLI (95% CI, .80-.89) and 0.78 for HSI (95% CI, .73-.83). Whereas FLI was well calibrated, HSI overestimated the risk for steatosis. Both models showed a positive net benefit, with FLI having a greater net benefit when compared with HSI. Conclusions: FLI and HSI are valid tools to detect liver steatosis in PWH. FLI should be the preferred score, given its better performance and greater clinical usefulness.
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Aim Recent developments in ultrasound elastography (UE) and ultrasound attenuation imaging (UA) have enabled the detection of advanced liver fibrosis and steatosis in patients with steatotic liver disease (SLD), which is prevalent worldwide. In patients with SLD, the presence of advanced liver fibrosis determines the risk of hepatocarcinogenesis, and UE and UA are expected to play important roles in liver cancer surveillance. We conducted a questionnaire survey among medical facilities in Saga Prefecture regarding the actual status of awareness and implementation of UE and UA. Methods A 16-item questionnaire was sent to 275 facilities that employed members of the Liver Cancer Control Medical Association in Saga Prefecture. The response rate was 56% (153 facilities), and data from 142 facilities were analyzed after excluding 11 facilities. Results The most common facilities were outpatient clinics (60%) followed by hospitals with ≥100 beds (14%). In 48% of the facilities, an average of 10-49 abdominal ultrasound examinations were performed monthly. The rates of recognition that UE and UA are useful for fibrosis and steatosis were 65% (92/142) and 41% (58/142), respectively. The actual availability of UE and UA in facilities with ultrasound machines was 21% (30/142) and 12% (17/142), respectively; UE and UA were used in 90% (27/30) and 88% (15/17) of these facilities, respectively. Conclusion Even among medical facilities in Saga Prefecture that are active in liver cancer surveillance, awareness of UE and UA is not high. The availability of UE and UA may be inadequate, considering the high prevalence of SLD.
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The function of hydroxysteroid dehydrogenase 12 (HSD17B12) in lipid metabolism is poorly understood. To study this further, we created mice with hepatocyte-specific knockout of HSD17B12 (LiB12cKO). From 2 months on, these mice showed significant fat accumulation in their liver. As they aged, they also had a reduced whole-body fat percentage. Interestingly, the liver fat accumulation did not result in the typical formation of large lipid droplets (LD); instead, small droplets were more prevalent. Thus, LiB12KO liver did not show increased macrovesicular steatosis with the increasing fat content, while microvesicular steatosis was the predominant feature in the liver. This indicates a failure in the LD expansion. This was associated with liver damage, presumably due to lipotoxicity. Notably, the lipidomics data did not support an essential role of HSD17B12 in fatty acid (FA) elongation. However, we did observe a decrease in the quantity of specific lipid species that contain FAs with carbon chain lengths of 18 and 20 atoms, including oleic acid. Of these, phosphatidylcholine and phosphatidylethanolamine have been shown to play a key role in LD formation, and a limited amount of these lipids could be part of the mechanism leading to the dysfunction in LD expansion. The increase in the Cidec expression further supported the deficiency in LD expansion in the LiB12cKO liver. This protein is crucial for the fusion and growth of LDs, along with the downregulation of several members of the major urinary protein family of proteins, which have recently been shown to be altered during endoplasmic reticulum stress.
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Hígado Graso , Hepatocitos , Gotas Lipídicas , Ratones Noqueados , Animales , Ratones , Gotas Lipídicas/metabolismo , Hepatocitos/metabolismo , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/genética , Metabolismo de los Lípidos , Peso Corporal , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ácidos Grasos/metabolismoRESUMEN
AIMS/INTRODUCTION: The 2023 Delphi consensus recommended the use of new term, metabolic dysfunction-associated steatotic liver disease (MASLD), aiming conceptual shift from the conventional non-alcoholic fatty liver disease (NAFLD). The association between NAFLD and type 2 diabetes mellitus (T2DM) development is well known. This study aimed to examine the correlation between MASLD and T2DM development, comparing their utility as predictors. MATERIALS AND METHODS: This retrospective cohort study obtained data from a medical health checkup program conducted at Asahi University Hospital, Japan, between 2004 and 2021. Logistic regression analysis was used to assess the association between MASLD and incident T2DM over 5 years. To compare the predictive utility of NAFLD and MASLD, receiver operating characteristic curves were drawn, followed by area under the curve (AUC) comparisons. RESULTS: In total, 15,039 participants (59.6% males; median [interquartile range {IQR}] age, 44 [38, 50] years) were included. Out of 2,682 participants meeting the criteria for MASLD, 234 individuals (8.7%) developed T2DM. Multivariate analysis revealed a significantly elevated risk of T2DM in MASLD compared with the reference healthy group (without steatotic liver disease or cardiometabolic risk), presenting an OR of 127.00 (95% CI 40.40-399.00, P < 0.001). The concordance rate of diagnosis between NAFLD and MASLD was 98.7%. The AUC values were 0.799 for NAFLD and 0.807 for MASLD, respectively. Comparative analysis of the AUC showed a statistical difference between NAFLD and MASLD (P < 0.001). CONCLUSIONS: MASLD was shown to be a significant risk factor for incident T2DM, exhibiting a potentially higher predictive capacity than conventional NAFLD.
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Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disorder marked by the buildup of triacylglycerols (TGs) in the liver. It includes a range of conditions, from simple steatosis to more severe forms like non-alcoholic steatohepatitis (NASH), which can advance to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD's prevalence is rising globally, estimated between 10% and 50%. The disease is linked to comorbidities such as obesity, type 2 diabetes, insulin resistance, and cardiovascular diseases and currently lacks effective treatment options. Therefore, researchers are focusing on evaluating the impact of adjunctive herbal therapies in individuals with NAFLD. One herbal therapy showing positive results in animal models and clinical studies is fruits from the Vaccinium spp. genus. This review presents an overview of the association between consuming fruits, juices, and extracts from Vaccinium spp. and NAFLD. The search used the following keywords: ((Vaccinium OR blueberry OR bilberry OR cranberry) AND ("non-alcoholic fatty liver disease" OR "non-alcoholic steatohepatitis")). Exclusion criteria included reviews, research notes, book chapters, case studies, and grants. The review included 20 studies: 2 clinical trials and 18 studies on animals and cell lines. The findings indicate that juices and extracts from Vaccinium fruits and leaves have significant potential in addressing NAFLD by improving lipid and glucose metabolism and boosting antioxidant and anti-inflammatory responses. In conclusion, blueberries appear to have the potential to alleviate NAFLD, but more clinical trials are needed to confirm these benefits.
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Frutas , Enfermedad del Hígado Graso no Alcohólico , Extractos Vegetales , Vaccinium , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/terapia , Humanos , Frutas/química , Vaccinium/química , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Fitoterapia , Jugos de Frutas y VegetalesRESUMEN
Intestinal dysbiosis and disrupted bile acid (BA) homeostasis are associated with obesity, but the precise mechanisms remain insufficiently explored. Hepatic protein phosphatase 1 regulatory subunit 3G (PPP1R3G) plays a pivotal role in regulating glycolipid metabolism; nevertheless, its obesity-combatting potency remains unclear. In this study, a substantial reduction was observed in serum PPP1R3G levels in high-body mass index (BMI) and high-fat diet (HFD)-exposed mice, establishing a positive correlation between PPP1R3G and non-12α-hydroxylated (non-12-OH) BA content. Additionally, hepatocyte-specific overexpression of Ppp1r3g (PPP1R3G HOE) mitigated HFD-induced obesity as evidenced by reduced weight, fat mass, and an improved serum lipid profile; hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology. PPP1R3G HOE considerably impacted systemic BA homeostasis, which notably increased the non-12-OH BAs ratio, particularly lithocholic acid (LCA). 16S ribosomal DNA (16S rDNA) sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population, and elevating the relative abundance of Blautia, which exhibited a positive correlation with serum LCA levels. A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent. Mechanistically, PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol-12α-hydroxylase (CYP8B1), and concurrently upregulated oxysterol 7-α hydroxylase and G protein-coupled BA receptor 5 (TGR5) expression under HFD conditions. Furthermore, LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels. These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis, which may serve as potential therapeutic targets for obesity-related disorders.
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Valproic acid (VPA), a common antiepileptic drug, can cause liver steatosis after long-term therapy. However, an impact of ferroptosis on VPA-induced liver steatosis has not been investigated. In the study, treatment with VPA promoted ferroptosis in the livers of mice by elevating ferrous iron (Fe2+) levels derived from the increased absorption by transferrin receptor 1 (TFR1) and the decreased storage by ferritin (FTH1 and FTL), disrupting the redox balance via reduced levels of solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPX4), and augmenting acyl-CoA synthetase long-chain family member 4 (ACSL4) -mediated lipid peroxide generation, accompanied by enhanced liver steatosis. All the changes were significantly reversed by co-treatment with an iron-chelating agent, deferoxamine mesylate (DFO) and a ferroptosis inhibitor, ferrostatin-1 (Fer-1). Similarly, the increases in Fe2+, TFR1, and ACSL4 levels, as well as the decreases in GSH, GPX4, and ferroportin (FPN) levels, were detected in VPA-treated HepG2 cells. These changes were also attenuated after co-treatment with Fer-1. It demonstrates that ferroptosis promotes VPA-induced liver steatosis through iron overload, inhibition of the GSH-GPX4 axis, and upregulation of ACSL4. It offers a potential therapy targeting ferroptosis for patients with liver steatosis following VPA treatment.
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Coenzima A Ligasas , Hígado Graso , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Receptores de Transferrina , Ácido Valproico , Ferroptosis/efectos de los fármacos , Animales , Ácido Valproico/toxicidad , Ratones , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Humanos , Hígado Graso/inducido químicamente , Hígado Graso/metabolismo , Masculino , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Hierro/metabolismo , Ratones Endogámicos C57BL , Ferritinas/metabolismo , Glutatión/metabolismo , Células Hep G2 , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Hígado/efectos de los fármacos , Hígado/metabolismoRESUMEN
Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.
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Mexican Americans are disproportionally affected by metabolic dysfunction-associated steatotic liver disease (MASLD), which often co-occurs with diabetes. Despite extensive evidence on the causative role of the gut microbiome in MASLD, studies determining the involvement of the gut phageome are scarce. In this cross-sectional study, we characterized the gut phageome in Mexican Americans of South Texas by stool shotgun metagenomic sequencing of 340 subjects, concurrently screened for liver steatosis by transient elastography. Inter-individual variations in the phageome were associated with gender, country of birth, diabetes, and liver steatosis. The phage signatures for diabetes and liver steatosis were subsequently determined. Enrichment of Inoviridae was associated with both diabetes and liver steatosis. Diabetes was further associated with the enrichment of predominantly temperate Escherichia phages, some of which possessed virulence factors. Liver steatosis was associated with the depletion of Lactococcus phages r1t and BK5-T, and enrichment of the globally prevalent Crassvirales phages, including members of genus cluster IX (Burzaovirus coli, Burzaovirus faecalis) and VI (Kahnovirus oralis). The Lactococcus phages showed strong correlations and co-occurrence with Lactococcus lactis, while the Crassvirales phages, B. coli, B. faecalis, and UAG-readthrough crAss clade correlated and co-occurred with Prevotella copri. In conclusion, we identified the gut phageome signatures for two closely linked metabolic diseases with significant global burden. These phage signatures may have utility in risk modeling and disease prevention in this high-risk population, and identification of potential bacterial targets for phage therapy.IMPORTANCEPhages influence human health and disease by shaping the gut bacterial community. Using stool samples from a high-risk Mexican American population, we provide insights into the gut phageome changes associated with diabetes and liver steatosis, two closely linked metabolic diseases with significant global burden. Common to both diseases was an enrichment of Inoviridae, a group of phages that infect bacterial hosts chronically without lysis, allowing them to significantly influence bacterial growth, virulence, motility, biofilm formation, and horizontal gene transfer. Diabetes was additionally associated with the enrichment of Escherichia coli-infecting phages, some of which contained virulence factors. Liver steatosis was additionally associated with the depletion of Lactococcus lactis-infecting phages, and enrichment of Crassvirales phages, a group of virulent phages with high global prevalence and persistence across generations. These phageome signatures may have utility in risk modeling, as well as identify potential bacterial targets for phage therapy.
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Bacteriófagos , Hígado Graso , Microbioma Gastrointestinal , Americanos Mexicanos , Viroma , Humanos , Masculino , Femenino , Microbioma Gastrointestinal/genética , Bacteriófagos/genética , Persona de Mediana Edad , Viroma/genética , Hígado Graso/genética , Estudios Transversales , Adulto , Diabetes Mellitus , Heces/microbiología , Heces/virología , AncianoRESUMEN
BACKGROUND & AIMS: There is a need to identify new treatment options for depression with its comorbidities. Depression often coexists with liver steatosis and the two may share a pathophysiological overlap, including inflammation and microbiota changes. Probiotics might represent a safe option as an adjunctive therapy in patients with depression and possible liver steatosis. The paper presents the secondary analysis of a clinical trial of the effect of probiotic supplementation on the levels of non-invasive markers of liver steatosis and fibrosis in adult patients with depressive disorders. METHODS: The research had a two-arm, parallel-group, prospective, randomized, double-blind, controlled design on probiotics in depression. 116 participants received a probiotic preparation containing Lactobacillus helveticus Rosell®-52 and Bifidobacterium longum Rosell®-175 over 60 days. Here, data from 92 subjects was analyzed. The following were assessed: alanine aminotransferase (ALT), alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio, Hepatic Steatosis Index, Framingham Steatosis Index, as well as non-invasive biomarkers of liver fibrosis (AST to Platelet Ratio Index, Fibosis-4 Index), or baseline socio-demographic, clinical, and laboratory parameters. RESULTS: The probiotics did not influence liver steatosis and fibrosis parameters compared with placebo (p = 0.940 for HSI). However, the subgroup analysis revealed significant differences in liver-related parameters when stratified by the main diagnosis group (better improvement in steatosis indices after probiotics in depressive episode than mixed depression and anxiety disorder patients) or psychotropic medications use (better improvement in ALT-based indices after probiotics in antidepressant-treated subjects than those non-antidepressant-treated). The interplay between probiotics, medications, clinical and metabolic profiles of depression, and the changes in liver-related parameters has been discussed. CONCLUSIONS: Multiple factors may modulate the postulated hepatoprotective properties of probiotics efficacy in patients with depression. Further studies with larger sample sizes, different probiotic strains, and longer intervention period are necessary to assess the real significance of probiotics for liver health in this population. GOV IDENTIFIER: NCT04756544.
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Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver alterations worldwide, being gut microbiota dysbiosis one of the contributing factors to its development. The aim of this research is to compare the potential effects of a viable probiotic (Lactobacillus rhamnosus GG) with those exerted by its heat-inactivated paraprobiotic counterpart in a dietary rodent model of NAFLD. The probiotic administration effectively prevented the hepatic lipid accumulation induced by a high-fat high-fructose diet feeding, as demonstrated by chemical (lower TG content) and histological (lower steatosis grade and lobular inflammation) analyses. This effect was mainly mediated by the downregulation of lipid uptake (FATP2 protein expression) and upregulating liver TG release to bloodstream (MTTP activity) in rats receiving the probiotic. By contrast, the effect of the paraprobiotic preventing diet-induced liver lipid accumulation was milder, and mainly derived from the downregulation of hepatic de novo lipogenesis (SREBP-1c protein expression and FAS activity) and TG assembly (DGAT2 and AQP9 protein expression). The obtained results demonstrate that under these experimental conditions, the effects induced by the administration of viable L. rhamnosus GG preventing liver lipid accumulation in rats fed a diet rich in saturated fat and fructose differ from those induced by its heat-inactivated paraprobiotic counterpart.
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OBJECTIVES: Currently, non-invasive scoring systems to stage the severity of non-alcoholic fatty liver disease (NAFLD) do not consider markers of glucose control (glycated haemoglobin, HbA1c); this study aimed to define the relationship between HbA1c and NAFLD severity in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were obtained from 857 patients with liver biopsy staged NAFLD. Generalized-linear models and binomial regression analysis were used to define the relationships between histological NAFLD severity, age, HbA1c, and BMI. Paired biopsies from interventional studies (nâ¯=â¯421) were used to assess the impact of change in weight, HbA1c and active vs. placebo treatment on improvements in steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. RESULTS: In the discovery cohort (nâ¯=â¯687), risk of severe steatosis, NASH and advanced fibrosis correlated positively with HbA1c, after adjustment for obesity and age. These data were endorsed in a separate validation cohort (nâ¯=â¯170). Predictive modelling using HbA1c and age was non-inferior to the established non-invasive biomarker, Fib-4, and allowed the generation of HbA1c, age, and BMI adjusted risk charts to predict NAFLD severity. Following intervention, reduction in HbA1c was associated with improvements in steatosis and NASH after adjustment for weight change and treatment, whilst fibrosis change was only associated with weight change and treatment. CONCLUSIONS: HbA1c is highly informative in predicting NAFLD severity and contributes more than BMI. Assessments of HbA1c must be a fundamental part of the holistic assessment of patients with NAFLD and, alongside age, can be used to identify patients with highest risk of advanced disease.
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Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. Portulaca oleracea exhibits anti-oxidant, anti-inflammatory, and hepatoprotective effects. This clinical trial aimed to investigate the potential benefits of Portulaca oleracea in improving NAFLD. Methods: This double-blind, randomized clinical trial enrolled 70 patients with NAFLD assigned to either the intervention group (n = 35) or placebo group (n = 35) using stratified block randomization. The intervention group received 700 mg Portulaca oleracea supplement for eight weeks, while the control group received placebo capsules. In addition, all participants received a calorie-restricted diet. Liver steatosis and fibrosis were assessed using elastography along with liver function and metabolic tests, blood pressure measurements, body composition analysis and dietary records pre-and post-intervention. Results: The average age of the participants was 44.01 ± 8.6 years, of which 34 (48.6%) were women. The group receiving Portulaca oleracea showed significant weight changes, body mass index, fat mass index, and waist circumference compared to the placebo (p < 0.001). In addition, blood sugar, lipid profile, liver enzymes aspartate and alanine transaminase, gamma-glutamyl transferase, and systolic blood pressure were significantly improved in the intervention group compared to those in the placebo (p < 0.05). During the study, inflammatory and oxidative stress indicators, improved significantly (p < 0.05). Based on the elastography results, the hepatorenal ultrasound index and liver stiffness decreased significantly in the Portulaca oleracea group compared to the placebo (p < 0.001). Conclusion: The present clinical trial showed that receiving Portulaca oleracea supplement for eight weeks can improve the condition of liver steatosis and fibrosis in patients with NAFLD.
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OBJECTIVES: To evaluate the diagnostic accuracy of liver dual-layer spectral-detector CT (SDCT) derived parameters of liver parenchyma for grading steatosis with reference to magnetic resonance imaging-based proton density fat fraction (MRI-PDFF). METHODS: Altogether, 320 consecutive subjects who underwent MRI-PDFF and liver SDCT examinations were recruited and prospectively enrolled from four Chinese hospital centers. Participants were classified into normal (n = 152), mild steatosis (n = 110), and moderate/severe(mod/sev) steatosis (n = 58) groups based on MRI-PDFF. SDCT liver parameters were evaluated using conventional polychromatic CT images (CTpoly), virtual mono-energetic images at 40 keV (CT40kev), the slope of the spectral attenuation curve (λ), the effective atomic number (Zeff), and liver to spleen attenuation ratio (L/S ratio). Linearity between SDCT liver parameters and MRI-PDFF was examined using Spearman correlation. Cutoff values for SDCT liver parameters in determining steatosis grades were identified using the area under the receiver-operating characteristic curve analyses. RESULTS: SDCT liver parameters demonstrated a strong correlation with PDFF, particularly Zeff (rs = -0.856; p < 0.001). Zeff achieved an area under the curve (AUC) of 0.930 for detecting the presence of steatosis with a sensitivity of 89.4%, a specificity of 82.4%, and an AUC of 0.983 for detecting mod/sev steatosis with a sensitivity of 93.1%, a specificity of 93.5%, the corresponding cutoff values were 7.12 and 6.94, respectively. Zeff also exhibited good diagnostic performance for liver steatosis grading in subgroups, independent of body mass index. CONCLUSION: SDCT liver parameters, particularly Zeff, exhibit excellent diagnostic accuracy for grading steatosis. CRITICAL RELEVANCE STATEMENT: Dual-layer SDCT parameter, Zeff, as a more convenient and accurate imaging biomarker may serve as an alternative indicator for MRI-based proton density fat fraction, exploring the stage and prognosis of liver steatosis, and even metabolic risk assessment. KEY POINTS: Liver biopsy is the standard for grading liver steatosis, but is limited by its invasive nature. The diagnostic performance of liver steatosis using SDCT-Zeff outperforms conventional CT parameters. SDCT-Zeff accurately and noninvasively assessed the grade of liver steatosis.
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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.
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Dieta Alta en Grasa , Fructosa , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Caracteres Sexuales , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Femenino , Masculino , Dieta Alta en Grasa/efectos adversos , Transducción de Señal/efectos de los fármacos , Ratas , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Autofagia/efectos de los fármacos , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratas Wistar , Estrés Oxidativo/efectos de los fármacos , Proteínas Asociadas a MicrotúbulosRESUMEN
BACKGROUND: Ramadan Intermittent fasting (RIF) exerts beneficial metabolic effects and improves gastrointestinal motility. However, a comparison between RIF and the traditional 16-hours intermittent fasting (16IF), a strategy for weight loss, is lacking. METHODS: A total of 34 subjects (median age 32.5 years, range 18-63 years; median BMI 24.5 Kg m-1², range 18.6-37.6 Kg m-1²) were assigned to RIF (N = 18) or 16IF (N = 16) for 30 days. We measured variations in anthropometric measures (BMI, waist, and abdominal circumference), serum insulin, glucose, cortisol, non-esterified fatty acid (NEFA), body fat composition (bioelectrical impedance analysis), and the ultrasonographic measurements of liver steatosis (Hepatorenal index, HRI) and thickness of subcutaneous (SAT) and visceral (VAT) fats. RESULTS: At baseline, BMI, rates of liver steatosis and distribution of normal weight, overweight, and obese subjects were comparable between the two groups. Body weight significantly decreased at the end of fasting in both RIF (-4.2 % vs baseline, P = 0.002) and 16IF (-2.1 % vs baseline, P = 0.002). Waist and abdominal circumferences significantly decreased only in RIF as well as the amount of body fat. In subjects with liver steatosis, SAT and VAT significantly decreased following RIF, but not 16h-IF, as well as the ultrasonographic HRI. CONCLUSION: Both 16IF and RIF are able, during 1-month, to reduce body weight. However, RIF but not 16IF also generates marked beneficial effects in terms of reduced subcutaneous fat and liver steatosis. Further studies urge to verify the effects of different models of IF in weight-cycling and long-term management of obesity and related dysmetabolic conditions, such as ectopic fat over-storage.
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Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
Asunto(s)
Ácidos y Sales Biliares , Humanos , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/inmunología , Animales , Microbioma Gastrointestinal/inmunologíaRESUMEN
Multiple modifications of metabolic syndrome diagnostic criteria have been made-NCEP: ATP III (from 2001, modified in 2004), IDF (2005), IDF Consortium (2009), or Polish Scientific Society Consortium standards (2022) are now frequently in use. Hepatosteatosis and hepatofibrosis are commonly mentioned aspects of metabolic syndrome that greatly increase the likelihood of developing complications. The objective of the study was to assess different diagnostic criteria for metabolic syndrome based on the prevalence of liver steatosis and fibrosis. A retrospective analysis was conducted on the medical data of 2102 patients. Out of all the single criteria, meeting the obesity criterion based on waist circumference showed the highest increase in the risk of hepatosteatosis (by 64-69%, depending on the definition used)-hypertriglyceridemia increased the risk of hepatofibrosis by 71%. Regardless of the specific criteria used, patients with metabolic syndrome had a 34-36% increased likelihood of developing hepatosteatosis-the probability of hepatofibrosis varied between 42% and 47% for the criteria established in 2004, 2005, and 2009, while the Polish 2022 criteria were not statistically significant (p = 0.818). It seems appropriate to establish consistent metabolic syndrome diagnostic criteria-the 2009 IDF guidelines are the most effective in assessing hepatosteatosis and fibrosis risk.
RESUMEN
Background/Objectives: Various biological response modifiers play important roles in the immunopathogenesis of chronic hepatitis C (CHC). While serum levels of cytokines and growth factors change with the disease severity and treatment responses, the impact of concomitant liver steatosis on systemic inflammatory response is largely unknown. The aim of this study was to analyze the characteristics and kinetics of serum profiles of interleukins and growth factors in CHC patients with steatotic liver disease (SLD). Methods: Serum concentrations of 12 cytokines (IL-5, IL-13, IL-2, IL-6, IL-9, IL-10, IFN-γ, TNF-α, IL-17A, IL-17F, IL-4 and IL-22) and 6 growth factors (Angiopoietin-2, EGF, EPO, HGF, SCF, VEGF) were analyzed in 56 CHC patients at four time points (baseline, week 4, week 8 and SVR12) with bead-based flow cytometry assay. Results: At baseline, patients with SLD had significantly lower IL-9, IL-10, IL-13 and IL-22 and higher serum concentrations of EGF, VEGF and ANG. In a subgroup of patients with advanced liver fibrosis, SLD was linked with lower serum concentrations of IL-4, IL-5, IL-9, IL-10, IL-13 and IL-22 and higher concentrations of HGH and VEGF. Distinct cytokine kinetics during DAA treatment was observed, and SLD was identified as the main source of variation for IL-5, IL-9, IL-10, IL-13, IL-17A, IL-22, EGF, VEGF and ANG. Patients with SLD at SVR12 had significantly higher VEGF and HGF serum concentrations. Conclusions: SLD is associated with distinct cytokine and growth factor profiles and kinetics during CHC treatment, which might be associated with disease severity and the capacity for liver regeneration and contribute to fibrosis persistence.