RESUMEN

Metabolic dysfunction-associated diseases often refer to various diseases caused by metabolic problems such as glucose and lipid metabolism disorders. With the improvement of living standards, the increasing prevalence of metabolic diseases has become a severe public health problem, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), diabetes and obesity. These diseases are both independent and interdependent, with complex and diverse molecular mechanisms. Therefore, it is urgent to explore the molecular mechanisms and find effective therapeutic targets of these diseases. MicroRNAs (miRNAs) have emerged as key regulators of metabolic homoeostasis due to their multitargets and network regulatory properties within the past few decades. In this review, we discussed the latest progress in the roles of miRNA-mediated regulatory networks in the development and progression of MASLD, ALD, diabetes and obesity.

Asunto(s)

Enfermedades Metabólicas , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Animales , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/terapia , Enfermedades Metabólicas/genética , Obesidad/metabolismo , Obesidad/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/terapia , Hígado Graso/etiología

RESUMEN

This study aimed to investigate the effect of Japanese dietary patterns on metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. After excluding factors affecting the diagnosis of hepatic steatosis, 727 adults were analyzed as part of the Health Promotion Project. The dietary patterns of the participants were classified into rice, vegetable, seafood, and sweet based on their daily food intake. Liver stiffness measurements and controlled attenuation parameters were performed using FibroScan. Energy and nutrient intake were calculated using the Brief-type Self-administered Diet History Questionnaire. Univariate and multivariate analyses were used to identify the risk factors for liver fibrosis within the MASLD population. The vegetable group had significantly lower liver fibrosis indicators in the MASLD population than the rice group. The multivariate analysis identified a body mass index ≥ 25 kg/m2 (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.01-1.83; p = 0.047) and HOMA-IR ≥ 1.6 (OR, 3.18; 95% CI, 1.74-5.78; p < 0.001) as risk factors for liver fibrosis, and vegetable group membership was a significant low-risk factor (OR, 0.38; 95% CI, 0.16-0.88; p = 0.023). The multivariate analysis of nutrients in low-risk foods revealed high intake of α-tocopherol (OR, 0.74; 95% CI, 0.56-0.99; p = 0.039) as a significant low-risk factor for liver fibrosis. This study suggests that a vegetable-based Japanese dietary pattern, through the antioxidant effects of α-tocopherol, may help prevent liver fibrosis in MASLD and the development of MASLD.

Asunto(s)

Dieta , Cirrosis Hepática , Humanos , Masculino , Femenino , Persona de Mediana Edad , Japón/epidemiología , Factores de Riesgo , Adulto , Dieta/efectos adversos , Verduras , Conducta Alimentaria , Índice de Masa Corporal , Anciano , Ingestión de Energía , Estudios Transversales , Hígado Graso/etiología , Patrones Dietéticos , Pueblos del Este de Asia

RESUMEN

Recently, we have demonstrated that mice, cultured embryos in α-minimum essential medium (αMEM) and subsequent fed a high-fat, high-sugar diet, developed steatohepatitis. In this study, we investigated using these samples whether the expression of lipid droplet formation genes in the liver is higher in MEM mice, whether these expressions are regulated by histone acetylation, writers/readers of histone acetylation, and the transcriptional factors of endoplasmic reticulum stress. Mice were produced by two-cell embryos in αMEM or standard potassium simplex-optimized medium (control) in vitro for 48 h, and implanted into an oviduct for spontaneous delivery. MEM and control-mice were fed a high-fat, high-sugar diet for 18 wk, and then liver samples were collected and analyzed by histology, qRT-PCR, and chromatin immunoprecipitation assay. Gene expression of Cidea, Cidec, and Plin4 were higher in MEM mice and histone H3K9 acetylation, BRD4, and CBP were higher in MEM mice than in control mice around those genes. However, the binding of endoplasmic reticulum stress-related transcription factors (ATF4, CHOP and C/EBPα) around those genes in the liver, was not clearly differed between MEM mice and control mice. The increased expression of Cidea, Cidec and Plin4 in the liver, accompanied by the development of steatohepatitis in mice induced is positively associated with increased histone H3K9 acetylation and CBP and BRD4 binding around these genes.

Asunto(s)

Estrés del Retículo Endoplásmico , Hígado Graso , Histonas , Gotas Lipídicas , Hígado , Animales , Histonas/metabolismo , Acetilación , Gotas Lipídicas/metabolismo , Ratones , Femenino , Hígado/metabolismo , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/etiología , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Dieta Alta en Grasa/efectos adversos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética

RESUMEN

OBJECTIVE: Both Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) are effective at inducing weight loss, but more information is needed on their comparative effectiveness at improving clinical/biochemical outcomes related to the presence of hyperlipidemia, metabolic dysfunction-associated steatotic liver disease (MASLD), or type 2 diabetes (T2D) at baseline. Here we aimed to assess this in real-world practice. METHODS: This is a prospective cross-sectional and cohort study of 142 patients who underwent RYGB or LSG as per clinical practice. Clinical/biochemical data were collected at baseline, prior to surgery and 12 months post-bariatric surgery. Liver biopsy was performed during surgery to diagnose MASLD. The main outcome was 12-month changes in lipid parameters, mainly total cholesterol, between types of surgery. RESULTS: A TOTAL OF: 107 participants underwent RYGB and 35 underwent LSG. Both groups were similar at baseline except for a higher proportion of males and waist circumference in the LSG group. At 12 months postsurgery, RYGB versus LSG resulted in a significantly lower body mass index, triglycerides, total cholesterol, and low-density lipoprotein. However, alanine aminotransferase was significantly lower in those who underwent LSG. In subgroup analyses RYGB was superior at improving lipid-related parameters in those with hyperlipidemia, whereas LSG was superior at reducing alanine aminotransferase in those with MASLD. CONCLUSIONS: RYGB versus LSG leads to greater reductions in body mass index and lipid parameters, especially in those with hyperlipidemia, whereas LSG showed greater improvements in liver enzymes in those with MASLD.

Asunto(s)

Diabetes Mellitus Tipo 2 , Gastrectomía , Derivación Gástrica , Hiperlipidemias , Humanos , Masculino , Femenino , Diabetes Mellitus Tipo 2/metabolismo , Hiperlipidemias/etiología , Estudios Prospectivos , Derivación Gástrica/métodos , Estudios Transversales , Persona de Mediana Edad , Adulto , Gastrectomía/métodos , Hígado Graso/etiología , Índice de Masa Corporal , Pérdida de Peso , Resultado del Tratamiento , Obesidad Mórbida/cirugía , Obesidad Mórbida/metabolismo , Obesidad Mórbida/complicaciones , Laparoscopía/métodos , Estudios de Cohortes

RESUMEN

Type 2 diabetes mellitus (T2DM), often featuring hyperglycemia or insulin resistance, is a global health concern that is increasing in prevalence in the United States and worldwide. A common complication is metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome that is also rapidly increasing in prevalence. The majority of patients with T2DM will experience MASLD, and likewise, individuals with MASLD are at an increased risk for developing T2DM. These two disorders may act synergistically, in part due to increased lipotoxicity and inflammation within the liver, among other causes. However, the pathophysiological mechanisms by which this occurs are unclear, as is how the improvement of one disorder can ameliorate the other. This review aims to discuss the pathogenic interactions between T2D and MASLD, and will highlight novel therapeutic targets and ongoing clinical trials for the treatment of these diseases.

Asunto(s)

Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Animales , Síndrome Metabólico/metabolismo , Síndrome Metabólico/complicaciones , Resistencia a la Insulina , Hígado Graso/metabolismo , Hígado Graso/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones

RESUMEN

Inhibiting diacylglycerol acetyltransferase (DGAT1, DGAT2) enzymes (iDGAT1, iDGAT2), involved in triglyceride (TG) synthesis, improves hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients. However, their potential synergism in disease onset (SLD) and progression (metabolic dysfunction-associated steatohepatitis, fibrosis) has been poorly explored. We investigated iDGAT1 and iDGAT2 efficacy, alone or combined (iDGAT1/2) on fat accumulation and hepatocellular injury in hepatocytes (HepG2) and on fibrogenic processes in hepatic stellate cells (LX2). We further tested whether the addition of MitoQ antioxidant to iDGAT1/2 would enhance their effects. SLD and MASH conditions were reproduced in vitro by supplementing Dulbecco's Modified Eagle's Medium (DMEM) with palmitic/oleic acids (PAOA) alone (SLD-medium), or plus Lipopolisaccaride (LPS), fructose, and glucose (MASH-medium). In SLD-medium, iDGAT1 and iDGAT2 individually, and even more in combination, reduced TG synthesis in HepG2 cells. Markers of hepatocellular damage were slightly decreased after single iDGAT exposure. Conversely, iDGAT1/2 counteracted ER/oxidative stress and inflammation and enhanced mitochondrial Tricarboxylic acid cycle (TCA) and respiration. In HepG2 cells under a MASH-like condition, only iDGAT1/2 effectively ameliorated TG content and oxidative and inflammatory mediators, further improving bioenergetic balance. LX2 cells, challenged with SLD/MASH media, showed less proliferation and slower migration rates in response to iDGAT1/2 drugs. MitoQ combined with iDGAT1/2 improved cell viability and dampened free fatty acid release by stimulating ß-oxidation. Dual DGAT inhibition combined with antioxidants open new perspectives for MASLD management.

Asunto(s)

Diacilglicerol O-Acetiltransferasa , Triglicéridos , Humanos , Diacilglicerol O-Acetiltransferasa/metabolismo , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Células Hep G2 , Triglicéridos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Hígado Graso/etiología , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos

RESUMEN

Both maternal obesity and postnatal consumption of obesogenic diets contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). However, there is no consensus as to whether diets that are high in fat or carbohydrates/sugars differentially influence the development of HCC. Moreover, the long-term effects of prenatal HF exposure on HCC and whether this is influenced by postnatal diet has not yet been evaluated. C57BL/6 dams were fed either a low-fat, high-carbohydrate control (C) or low-carbohydrate, high-fat (HF) diet. At weaning, male and female offspring were fed the C or HF diet, generating four diet groups: C/C, C/HF, HF/C and HF/HF. Tissues were collected at 16 months of age and livers were assessed for MASLD and HCC. Glucose regulation and pancreatic morphology were also evaluated. Liver tissues were assessed for markers of glycolysis and fatty acid metabolism and validated using a human HCC bioinformatic database. Both C/HF and HF/HF mice developed obesity, hyperinsulinemia and a greater degree of MASLD than C/C and HF/C offspring. However, despite significant liver and pancreas pathology, C/HF mice had the lowest incidence of HCC while tumour burden was highest in HF/C male offspring. The molecular profile of HCC mouse samples suggested an upregulation of the pentose phosphate pathway and a downregulation of fatty acid synthesis and oxidation, which was largely validated in the human dataset. Both pre-weaning HF diet exposure and post-weaning consumption of a high-carbohydrate diet increased the risk of developing spontaneous HCC in aged mice. However, the influence of pre-weaning HF feeding on HCC development appeared to be stronger in the context of post-weaning obesity. As rates of maternal obesity continue to rise, this has implications for the future incidence of HCC and possible dietary manipulation of offspring carbohydrate intake to counteract this risk.

Asunto(s)

Carcinoma Hepatocelular , Dieta Alta en Grasa , Neoplasias Hepáticas , Ratones Endogámicos C57BL , Destete , Animales , Femenino , Dieta Alta en Grasa/efectos adversos , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Embarazo , Masculino , Ratones , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiologicos Nutricionales Maternos , Hígado/metabolismo , Hígado/patología , Obesidad , Hígado Graso/etiología , Carbohidratos de la Dieta/efectos adversos , Carbohidratos de la Dieta/administración & dosificación

RESUMEN

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.

Asunto(s)

Alimentación Animal , Aceites de Pescado , Aceite de Brassica napus , Salmo salar , Animales , Aceite de Brassica napus/administración & dosificación , Salmo salar/metabolismo , Salmo salar/crecimiento & desarrollo , Aceites de Pescado/administración & dosificación , Alimentación Animal/análisis , Ácidos Grasos/metabolismo , Ácidos Grasos/análisis , Enfermedades de los Peces/patología , Enfermedades de los Peces/metabolismo , Hígado Graso/veterinaria , Hígado Graso/metabolismo , Hígado Graso/etiología , Hígado Graso/patología , Colina/metabolismo , Colina/administración & dosificación , Dieta/veterinaria , Hígado/metabolismo , Hígado/patología

RESUMEN

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.

Asunto(s)

Ratones Endogámicos C57BL , Obesidad , Linfocitos T , Animales , Obesidad/inmunología , Obesidad/complicaciones , Obesidad/etiología , Femenino , Masculino , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Dieta Alta en Grasa/efectos adversos , Factores Sexuales , Bazo/inmunología , Bazo/patología , Caracteres Sexuales , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Hígado Graso/etiología , Hígado Graso/inmunología , Hígado Graso/patología , Inflamación/inmunología , Inflamación/patología , Inflamación/etiología

RESUMEN

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant and ever-increasing health and economic burden worldwide. Substantial epidemiological evidence shows that MASLD is a multisystem disease that is associated not only with liver-related complications but is also associated with an increased risk of developing cardiometabolic comorbidities and extrahepatic cancers (principally gastrointestinal [GI] cancers). GI cancers account for a quarter of the global cancer incidence and a third of cancer-related deaths. In this narrative review, we provide an overview of the literature on (a) the epidemiological data on the risk of non-liver GI cancers in MASLD, (b) the putative mechanisms by which MASLD (and factors linked with MASLD) may increase this risk, and (c) the possible pharmacotherapies beneficially affecting both MASLD and extrahepatic GI cancer risk. There are multiple potential pathophysiological mechanisms by which MASLD may increase extrahepatic GI cancer risk. Although further studies are needed, the current evidence supports a possible extrahepatic carcinogenic role for MASLD, regardless of obesity and diabetes status, thus highlighting the potential role of tailoring cancer screening for individuals with MASLD. Although there are conflicting data in the literature, aspirin, statins and metformin appear to exert some chemo-preventive effects against GI cancer.

Asunto(s)

Hígado Graso , Neoplasias Gastrointestinales , Humanos , Neoplasias Gastrointestinales/etiología , Neoplasias Gastrointestinales/epidemiología , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/complicaciones , Neoplasias Gastrointestinales/patología , Hígado Graso/complicaciones , Hígado Graso/epidemiología , Hígado Graso/etiología , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/etiología , Factores de Riesgo

RESUMEN

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-ß agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD - 27.74 (95% CI - 32.05 to - 32.42), p < 0.00001] at 36-52 weeks as well as at 12-16 weeks [SMD - 30.92 (95% CI - 36.44 to - 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36-52 weeks [SMD - 36.05 (95% CI - 40.67 to - 31.43), p < 0.00001] and 12-16 weeks [SMD - 36.89 (95% CI - 40.73 to - 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD.

Asunto(s)

Hígado Graso , Piridazinas , Receptores beta de Hormona Tiroidea , Humanos , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/metabolismo , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores beta de Hormona Tiroidea/agonistas , Resultado del Tratamiento , Uracilo/administración & dosificación , Uracilo/efectos adversos , Uracilo/análogos & derivados

RESUMEN

Cordyceps guangdongensis, a novel edible mushroom in China, has shown many positive health effects. In this study, we extracted the C. guangdongensis polysaccharides (CGP) from the fruiting bodies, and investigated the mechanism for CGP improved high-fat diet-induced (HFDI) metabolic diseases. We found that CGP notably reduced fat mass, improved blood lipid levels and hepatic damage, and restored the gut microbiota dysbiosis induced by high-fat diet (HFD). Metabolome analyses showed that CGP changed the composition of bile acids, and regulated HFDI metabolic disorder in hepatic tissue. Transcriptome comparison showed that the improvement of hepatic steatosis for CGP was mainly related to lipid and carbohydrate metabolism. Association analysis result revealed that Odoribacter, Bifidobacterium and Bi. pseudolongum were negatively correlated to fat and blood lipid indicators, and were significantly associated with genes and metabolites related to carbohydrate and lipid metabolism. Collectively, these results indicate that CGP may be a promising supplement for the treatment of obesity and related metabolic diseases.

Asunto(s)

Cordyceps , Dieta Alta en Grasa , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Cordyceps/química , Ratones , Dieta Alta en Grasa/efectos adversos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Polisacáridos Fúngicos/farmacología , Polisacáridos Fúngicos/química , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/metabolismo , Metaboloma/efectos de los fármacos , Ratones Endogámicos C57BL , Polisacáridos/farmacología , Polisacáridos/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Disbiosis

RESUMEN

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a disease that causes an abnormal accumulation of fat in the liver, triggering inflammation and fibrosis, the mechanism of which is not fully understood and for which there is a lack of specific drug therapy. Far-infrared radiation (FIR) has demonstrated evident therapeutic efficacy across various diseases, and novel nanomaterial graphene patches can emit it through electric heating. This study aimed to investigate the potential protective effects of FIR against MAFLD. Mice were fed with a MCD diet to mimic MAFLD progression, and histopathology analysis, biochemical analysis, RT-qPCR, and Western blotting analysis were performed to assess the effect of FIR on MAFLD in vivo. The effect of FIR treatment on MAFLD in vitro was investigated by biochemical analysis and gene expression profiling of hepatocytes. Mice subjected to the MCD diet and treated with FIR exhibited reduced hepatic lipid deposition, inflammation, fibrosis and liver damage. The therapeutic effect exerted by FIR in mice may be caused by the enhancement of AMPK phosphorylation and inhibition of the TGFß1-SMAD2/3 pathway. Besides, FIR intervention alleviated MAFLD in hepatocytes in vitro and the results were verified by gene expression profiling. Our results revealed a promising potential of FIR as a novel therapeutic approach for MAFLD.

Asunto(s)

Hepatocitos , Rayos Infrarrojos , Cirrosis Hepática , Animales , Ratones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/etiología , Hepatocitos/metabolismo , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/etiología , Hígado/metabolismo , Hígado/patología , Hígado/efectos de la radiación , Transducción de Señal , Proteína smad3/metabolismo , Proteína Smad2/metabolismo , Fosforilación

RESUMEN

BACKGROUND AND AIMS: Biopsy-proven severe graft steatosis is associated with adverse outcomes after liver transplantation. The concomitant presence of metabolic risk factors might further increase this risk. We studied the association between graft steatosis and metabolic risk factors in the donor, with recipient outcomes after liver transplantation. METHODS: We analyzed data from all consecutive first adult full-graft donation after brain death (DBD) liver transplantations performed in the Eurotransplant region between 2010 and 2020. The presence of graft steatosis and metabolic risk factors was assessed through a review of donor (imaging) reports, and associations with recipient retransplantation-free survival were studied through survival analyses. RESULTS: Of 12 174 transplantations, graft steatosis was detected in 2689 (22.1%), and donor diabetes mellitus (DM), hypertension, and dyslipidemia were present in 1245 (10.2%), 5056 (41.5%), and 524 (4.3%). In multivariable Cox regression analysis, graft steatosis (adjusted HR [aHR] 1.197, p < 0.001) and donor DM (aHR 1.157, p = 0.004) were independently associated with impaired retransplantation-free survival. Graft steatosis and donor DM conferred an additive risk of retransplantation or death (DM alone, aHR: 1.156 [p = 0.0185]; steatosis alone, aHR: 1.200 [p < 0.001]; both steatosis and DM, aHR: 1.381 [p < 0.001]). Findings were consistent in sensitivity analyses focusing on retransplantation-free survival within 7 days. CONCLUSIONS: Graft steatosis and donor diabetes mellitus additively increase the risk of retransplantation or death in adult DBD liver transplantation. Future studies should focus on methods to assess and improve the quality of these high-risk grafts. Until such time, caution should be exercised when considering these grafts for transplantation.

Asunto(s)

Hígado Graso , Supervivencia de Injerto , Trasplante de Hígado , Complicaciones Posoperatorias , Sistema de Registros , Donantes de Tejidos , Humanos , Femenino , Masculino , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Persona de Mediana Edad , Hígado Graso/patología , Hígado Graso/etiología , Hígado Graso/complicaciones , Hígado Graso/cirugía , Donantes de Tejidos/provisión & distribución , Factores de Riesgo , Estudios de Seguimiento , Pronóstico , Adulto , Europa (Continente)/epidemiología , Tasa de Supervivencia , Diabetes Mellitus , Rechazo de Injerto/etiología , Rechazo de Injerto/mortalidad , Estudios Retrospectivos , Receptores de Trasplantes/estadística & datos numéricos

RESUMEN

This study investigates sex-specific effects in a gain-of-function model to evaluate Nfil3 function in relation to high-fat diet (HFD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) and gut microbiota (GM)-induced alterations in the bile acid (BA) profile. MASLD is induced in both wild type and Nfil3-deficient (NKO) C57BL/6 J mice through an HFD. The hepatic immune response is evaluated using flow cytometry, revealing that NKO mice exhibit lower body weight, serum triglyceride (TG) levels, tissue injury, inflammation, and fat accumulation. The Nfil3 deletion reduces macrophage counts in fibrotic liver tissues, decreases proinflammatory gene and protein expression, and diminishes gut barrier function. Alpha and beta diversity analysis reveal increased GM alpha diversity across different sexes. The Nfil3 gene deletion modifies the BA profile, suggesting that negative feedback through the Nfil3-FXR-FGF15 axis facilitates BA recycling from the liver via enterohepatic circulation. Therefore, inhibiting Nfil3 in the liver offers a viable treatment approach for MASLD.

Asunto(s)

Dieta Alta en Grasa , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Ratones , Masculino , Femenino , Dieta Alta en Grasa/efectos adversos , Microbioma Gastrointestinal , Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Hígado Graso/genética , Hígado Graso/patología , Hígado Graso/etiología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico

RESUMEN

The mitochondrial citrate shuttle, which relies on the solute carrier family 25 member 1 (SLC25A1), plays a pivotal role in transporting citrate from the mitochondria to the cytoplasm. This shuttle supports glycolysis, lipid biosynthesis, and protein acetylation. Previous research has primarily focused on SLC25A1 in pathological models, particularly high-fat diet (HFD)-induced obesity. However, the impact of SLC25A1 inhibition on nutrient metabolism under HFD remains unclear. To address this gap, we used zebrafish (Danio rerio) and Nile tilapia (Oreochromis niloticus) to evaluate the effects of inhibiting Slc25a1. In zebrafish, we administered Slc25a1-specific inhibitors (CTPI-2) for 4 wk, whereas Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibition of the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance. Of note, glucose tolerance was unaffected. Inhibition of Slc25a1 altered hepatic protein acetylation patterns, with decreased cytoplasmic acetylation and increased mitochondrial acetylation. Under HFD conditions, Slc25a1 inhibition promoted fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). In addition, Slc25a1 inhibition triggered acetylation-induced inactivation of Pdhe1α, leading to a reduction in glucose oxidative catabolism. This was accompanied by enhanced glucose uptake and storage in zebrafish livers. Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and enhancing oxidative phosphorylation for energy production. Our findings provide new insights into the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD.NEW & NOTEWORTHY The mitochondrial citrate shuttle is a crucial physiological process for maintaining metabolic homeostasis. In the present study, we found that inhibition of mitochondrial citrate shuttle (Slc25a1) could alleviate metabolic syndromes induced by high-fat diet (HFD) through remodeling hepatic protein acetylation modification. Briefly, Slc25a1 inhibition reduces hepatic triglyceride deposition by deacetylating Cpt1a and reduces glucose oxidative catabolism by acetylating Pdhe1α. Our study provides new insights into the treatment of diet-induced metabolic syndromes.

Asunto(s)

Ácido Cítrico , Dieta Alta en Grasa , Pez Cebra , Animales , Dieta Alta en Grasa/efectos adversos , Ácido Cítrico/metabolismo , Síndrome Metabólico/metabolismo , Síndrome Metabólico/prevención & control , Síndrome Metabólico/genética , Síndrome Metabólico/etiología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Obesidad/metabolismo , Obesidad/prevención & control , Obesidad/genética , Obesidad/etiología , Acetilación , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Resistencia a la Insulina , Hígado Graso/metabolismo , Hígado Graso/prevención & control , Hígado Graso/patología , Hígado Graso/etiología , Metabolismo de los Lípidos/efectos de los fármacos

RESUMEN

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health problem. Dietary intervention plays an important role in patients with MAFLD. OBJECTIVES: We aimed to provide a reference for dietary patterns in patients with MAFLD. METHODS: The presence of MAFLD was determined in the United Kingdom Biobank cohort. Nine dietary pattern scores were derived from the dietary records. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The contrast test was employed to calculate the heterogeneity across MAFLD statuses. RESULTS: We identified 175,300 patients with MAFLD at baseline. Compared with non-MAFLD, MAFLD was significantly associated with chronic liver disease (CLD) (HR: 3.48; 95% CI: 3.15, 3.84), severe liver disease (SLD) (HR: 2.87; 95% CI: 2.63, 3.14), liver cancer (HR: 1.93; 95% CI: 1.67, 2.23), and liver-related death (LRD) (HR: 1.93; 95% CI: 1.67, 2.23). In the overall cohort, the alternate Mediterranean diet (aMED) (HRCLD: 0.53; 95% CI: 0.37, 0.76; HRSLD: 0.52; 95% CI: 0.37, 0.72), planetary health diet (PHD) (HRCLD: 0.62; 95% CI: 0.47, 0.81; HRSLD: 0.65; 95% CI: 0.51, 0.83), plant-based low-carbohydrate diet (pLCD) (HRCLD: 0.65; 95% CI: 0.49, 0.86; HRSLD: 0.66; 95% CI: 0.51, 0.85), and healthful plant-based diet index (hPDI) (HRCLD: 0.63; 95% CI: 0.47, 0.84; HRSLD: 0.61; 95% CI: 0.47, 0.78) were associated with a lower risk of CLD and SLD. Additionally, unhealthful plant-based diet index (uPDI) was associated with increased risk of CLD (HR: 1.42; 95% CI: 1.09,1.85), SLD (HR: 1.50; 95% CI: 1.19, 1.90), and LRD (HR: 1.88; 95% CI: 1.28-2.78). The aforementioned associations remained consistently strong within the MAFLD subgroup while exhibiting less pronounced in the non-MAFLD group. However, no significant heterogeneity was observed across different MAFLD statuses. CONCLUSIONS: These findings highlight the detrimental effects of MAFLD on the development of subsequent liver diseases and the importance of dietary patterns in managing MAFLD.

Asunto(s)

Dieta , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Estudios de Cohortes , Adulto , Reino Unido/epidemiología , Progresión de la Enfermedad , Hígado Graso/etiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Hepatopatías/etiología , Hepatopatías/epidemiología , Patrones Dietéticos

RESUMEN

Objective: Non-alcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (ALD) are the most common chronic liver diseases. Hepatic steatosis is an early histological subtype of both NAFLD and ALD. Excessive alcohol consumption is widely known to lead to hepatic steatosis and subsequent liver damage. However, reported findings concerning the association between moderate alcohol consumption and hepatic steatosis remain inconsistent. Notably, alcohol consumption as a modifiable lifestyle behavior is likely to change over time, but most previous studies covered alcohol intake only once at baseline. These inconsistent findings from existing studies do not inform decision-making concerning policies and clinical guidelines, which are of greater interest to health policymakers and clinician-scientists. Additionally, recommendations on the types of alcoholic beverages are not available. Usually, assessing the effects of two or more hypothetical alcohol consumption interventions on hepatic steatosis provides answers to questions concerning the population risk of hepatic steatosis if everyone changes from heavy drinking to abstinence, or if everyone keeps on drinking moderately, or if everyone of the drinking population switches from red wine to beer? Thus, we simulated a target trial to estimate the effects of several hypothetical interventions, including changes in the amount of alcohol consumption or the types of alcoholic beverages consumed, on hepatic steatosis using longitudinal data, to inform decisions about alcohol-related policymaking and clinical care. Methods: This longitudinal study included 12687 participants from the UK Biobank (UKB), all of whom participated in both baseline and repeat surveys. We excluded participants with missing data related to components of alcohol consumption and fatty liver index (FLI) in the baseline and the repeat surveys, as well as those who had reported liver diseases or cancer at the baseline survey. We used FLI as an outcome indicator and divided the participants into non-, moderate, and heavy drinkers. The surrogate marker FLI has been endorsed by many international organizations' guidelines, such as the European Association for the Study of the Liver. The calculation of FLI was based on laboratory and anthropometric data, including triglyceride, gamma-glutamyl transferase, body mass index, and waist circumference. Participants responded to questions about the types of alcoholic beverages, which were defined in 5 categories, including red wine, white wine/fortified wine/champagne, beer or cider, spirits, and mixed liqueurs, along with the average weekly or monthly amounts of alcohol consumed. Alcohol consumption was defined as pure alcohol consumed per week and was calculated according to the amount of alcoholic beverages consumed per week and the average ethanol content by volume in each alcoholic beverage. Participants were categorized as non-drinkers, moderate drinkers, and heavy drinkers according to the amount of their alcohol consumption. Moderate drinking was defined as consuming no more than 210 g of alcohol per week for men and 140 g of alcohol per week for women. We defined the following hypothetical interventions for the amount of alcohol consumed: sustaining a certain level of alcohol consumption from baseline to the repeat survey (e.g., none to none, moderate to moderate, heavy to heavy) and changing from one alcohol consumption level to another (e.g., none to moderate, moderate to heavy). The hypothetical interventions for the types of alcoholic beverages were defined in a similar way to those for the amount of alcohol consumed (e.g., red wine to red wine, red wine to beer/cider). We applied the parametric g-formula to estimate the effect of each hypothetical alcohol consumption intervention on the FLI. To implement the parametric g-formula, we first modeled the probability of time-varying confounders and FLI conditional on covariates. We then used these conditional probabilities to estimate the FLI value if the alcohol consumption level of each participant was under a specific hypothetical intervention. The confidence interval was obtained by 200 bootstrap samples. Results: For the alcohol consumption from baseline to the repeat surveys, 6.65% of the participants were sustained non-drinkers, 63.68% were sustained moderate drinkers, and 14.74% were sustained heavy drinkers, while 8.39% changed from heavy drinking to moderate drinking. Regarding the types of alcoholic beverages from baseline to the repeat surveys, 27.06% of the drinkers sustained their intake of red wine. Whatever the baseline alcohol consumption level, the hypothetical interventions for increasing alcohol consumption from the baseline alcohol consumption were associated with a higher FLI than that of the sustained baseline alcohol consumption level. When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to moderate drinking, the mean ratio of FLI was 1.027 (95% confidence interval [CI]: 0.997-1.057). When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to heavy drinking, the mean ratio of FLI was 1.075 (95% CI: 1.042-1.108). When comparing sustained heavy drinking with the hypothetical intervention of changing from heavy drinking to moderate drinking, the mean ratio of FLI was 0.953 (95% CI: 0.938-0.968). The hypothetical intervention of changing to red wine in the UKB was associated with lower FLI levels, compared with sustained consumption of other types of alcoholic beverages. For example, when comparing sustaining spirits with the hypothetical intervention of changing from spirits to red wine, the mean ratio of FLI was 0.981 (95% CI: 0.948-1.014). Conclusions: Regardless of the current level of alcohol consumption, interventions that increase alcohol consumption could raise the risk of hepatic steatosis in Western populations. The findings of this study could inform the formulation of future practice guidelines and health policies. If quitting drinking is challenging, red wine may be a better option than other types of alcoholic beverages in Western populations.

Asunto(s)

Consumo de Bebidas Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Estudios Longitudinales , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Masculino , Femenino , Bebidas Alcohólicas/efectos adversos , Hígado Graso Alcohólico/etiología , Persona de Mediana Edad , Hígado Graso/etiología , Estudios de Cohortes

RESUMEN

Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH-associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western-type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper-iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA-fed and CuD-fed mice under RA. However, in IH exposure, CuD-fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA-fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD-treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator-activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis-promoting factor arachidonyl-CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD-induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH-associated MAFLD.

Asunto(s)

Cobre , Ferroptosis , Hipoxia , Ratones Endogámicos C57BL , Animales , Cobre/metabolismo , Cobre/deficiencia , Masculino , Ratones , Hipoxia/metabolismo , Humanos , Células Hep G2 , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo , Metabolismo de los Lípidos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/etiología , Hierro/metabolismo , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , PPAR alfa/metabolismo , PPAR alfa/genética

RESUMEN

Metabolic dysfunction-associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic liver disease in the United States and worldwide due to the obesity and diabetes epidemics. It is estimated that by 2030 close to 100 million people might be affected and patients with type 2 diabetes are especially at high risk. Twenty to 30% of patients with MASLD can progress to MASH, which is characterized by steatosis, necroinflammation, hepatocyte ballooning, and in advanced cases, fibrosis progressing to cirrhosis. Clinically, it is recognized that disease progression in diabetic patients is accelerated and the role of various genetic and epigenetic factors, as well as cell-matrix interactions in fibrosis and stromal remodeling, have recently been recognized. While there has been great progress in drug development and clinical trials for MASLD/MASH, the complexity of these pathways highlights the need to improve diagnosis/early detection and develop more successful antifibrotic therapies that not only prevent but reverse fibrosis.

Asunto(s)

Diabetes Mellitus Tipo 2 , Cirrosis Hepática , Humanos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Progresión de la Enfermedad , Animales , Matriz Extracelular/metabolismo , Hígado Graso/metabolismo , Hígado Graso/etiología