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2.
Biomolecules ; 14(4)2024 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-38672492

RESUMEN

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.


Asunto(s)
Inmunidad Innata , Humanos , Animales , Hígado Graso/inmunología , Inflamasomas/inmunología , Inflamasomas/metabolismo , Citocinas/metabolismo , Citocinas/inmunología , Resistencia a la Insulina/inmunología , Inflamación/inmunología
3.
iScience ; 27(3): 109173, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38496294

RESUMEN

Inflammatory bowel diseases are characterized by the chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER stress on the pathophysiology of IBD remain unclear. By using in vitro, in vivo models, and patient datasets, we identified a distinct polarization of the mitochondrial one-carbon metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon ER stress. This metabolic phenotype strongly correlates with IBD severity and therapy response. Mechanistically, we uncover that both chronic ER stress and serine limitation disrupt cGAS-STING signaling, impairing the epithelial response against viral and bacterial infection and fueling experimental enteritis. Consequently, the antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of serine metabolism to allow proper cGAS-STING signaling and innate immune responses upon gut inflammation.

4.
Trends Cell Biol ; 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38341347

RESUMEN

The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host-microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future.

5.
Expert Rev Clin Immunol ; 20(4): 375-386, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38149354

RESUMEN

INTRODUCTION: Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease - MASLD; metabolic dysfunction-associated steatohepatitis - MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts. AREAS COVERED: We summarize the pathophysiologic concepts of MASLD and its transition to MASH and subsequent advanced sequelae of diseases. Furthermore, we highlight how dietary constituents, microbes and associated metabolites, metabolic perturbations, and immune dysregulation fuel lipotoxicity, hepatic inflammation, liver injury, insulin resistance, and systemic inflammation. Deciphering the intricate pathophysiologic processes that contribute to the development and progression of MASLD is essential to develop targeted therapeutic approaches to combat this escalating burden for health-care systems. EXPERT OPINION: The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease challenges health-care systems worldwide. Understanding pathophysiologic traits is crucial to improve the prevention and treatment of this disorder and to slow progression into advanced sequelae such as cirrhosis and hepatocellular carcinoma.


Asunto(s)
Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Humanos , Cirrosis Hepática , Progresión de la Enfermedad , Inflamación
6.
JHEP Rep ; 5(11): 100872, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37818230

RESUMEN

Background & Aims: Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods: NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results: NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1ß, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions: NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications: Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.

8.
Commun Biol ; 5(1): 1391, 2022 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-36539532

RESUMEN

Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.


Asunto(s)
Citocinas , Péptidos y Proteínas de Señalización Intercelular , Humanos , Animales , Ratones , Péptidos y Proteínas de Señalización Intercelular/genética , Línea Celular Tumoral , Transducción de Señal , Inflamación/genética
9.
Ther Adv Endocrinol Metab ; 13: 20420188221139101, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36439029

RESUMEN

Metabolic dysfunction-associated fatty liver disease (MAFLD) has appeared as the leading liver disease worldwide. Whereas the terminology nonalcoholic fatty liver disease (NAFLD) mainly reflected a negative selection and exclusion of alcohol-related liver disease (ALD), the new definition made its focus on the association of MAFLD with overweight/obesity, type 2 diabetes and metabolic risk factors especially also in normal weight/lean subjects. Several studies from the past 2 years have now used the new definition and have provided substantial information that this new definition might be accurate. Studies from the past 2 years have provided evidence that the new definition might be especially advantageous in the characterization and identification of patients with significant fibrosis. This has also been demonstrated in the well-known Rotterdam study in which the MAFLD-only group showed a higher rate of fibrosis and liver stiffness. MAFLD might also be able to predict all-cause mortality as demonstrated in the Third National Health and Nutrition Examination Survey. Furthermore, MAFLD might improve characterization of the cardiovascular risk of this patient population. As the term MAFLD has not yet been accepted universally, it remains important to coordinate efforts globally to adapt to this new definition and especially involve all specialities dealing with metabolic disorders such as diabetologists to further improve its definition and to prepare the medical community for its future use. The aim of this review is to summarize and critically address evidence emerging over the past 2 years that usage of the term MAFLD could be helpful in daily clinical practice.

10.
Gut Microbes ; 14(1): 2089006, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35786161

RESUMEN

Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. Bacteroides thetaiotaomicron (Bt) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of Bt in the genesis of ethanol-induced liver steatosis. Bt DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living Bt, followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced Bt abundance, which was preserved by Bt oral supplementation. Bt-treated mice displayed lower hepatic steatosis and triglyceride content. Bt restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, Bt up-regulated Glucagon-like peptide-1 (GLP-1) expression and restored ethanol-induced Fibroblast growth factor 15 (FGF15) down-regulation. Lipid metabolism was consequently affected as Bt administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with Bt preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced Bt depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. Bt could serve as a novel probiotic to treat ALD in the future.


Asunto(s)
Bacteroides thetaiotaomicron , Hígado Graso , Microbioma Gastrointestinal , Hepatopatías , Animales , Etanol/toxicidad , Ratones , Triglicéridos
11.
Nat Rev Gastroenterol Hepatol ; 19(12): 753-767, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35906289

RESUMEN

Crohn's disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism. Genetic IBD risk partly affects metabolism and stress signalling of innate immunity, and immunometabolism controls susceptibility to gut inflammation. Epidemiological and clinical studies indicate that specific nutrients in the Western diet pose a risk for the development of IBD and a poor disease course. Translational studies in IBD indicate perturbation of energy metabolism in immune cells and perturbation of gut microbial metabolism, which can be shaped by diet. In turn, dietary restriction by exclusive enteral nutrition induces remission in patients with IBD. Collectively, these studies support a metabolic underpinning of gut inflammation in IBD as described for metabolic inflammation in obesity and related disorders.


Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/genética , Dieta , Inflamación
12.
Gastroenterology ; 163(4): 1120-1121, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35760088
13.
Gastroenterology ; 162(6): 1690-1704, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35031299

RESUMEN

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.


Asunto(s)
Enfermedad de Crohn , Enteritis , Ácidos Grasos Omega-3 , Animales , Enfermedad de Crohn/tratamiento farmacológico , Endorribonucleasas , Enteritis/inducido químicamente , Enteritis/tratamiento farmacológico , Ácidos Grasos Insaturados , Humanos , Inflamación/tratamiento farmacológico , Ratones , Proteínas Serina-Treonina Quinasas , Receptor Toll-Like 2
14.
Int J Obes (Lond) ; 46(5): 951-959, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35031697

RESUMEN

OBJECTIVES: Metabolic inflammation is a hallmark of obesity and related disorders, afflicting substantial morbidity and mortality to individuals worldwide. White visceral and subcutaneous adipose tissue not only serves as energy storage but also controls metabolism. Adipose tissue inflammation, commonly observed in human obesity, is considered a critical driver of metabolic perturbation while molecular hubs are poorly explored. Metabolic stress evoked by e.g. long-chain fatty acids leads to oxidative perturbation of adipocytes and production of inflammatory cytokines, fuelling macrophage infiltration and systemic low-grade inflammation. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation, accumulation of oxygen-specific epitopes and cell death, collectively referred to as ferroptosis. Here, we explore the function of adipocyte GPX4 in mammalian metabolism. METHODS: We studied the regulation and function of GPX4 in differentiated mouse adipocytes derived from 3T3-L1 fibroblasts. We generated two conditional adipocyte-specific Gpx4 knockout mice by crossing Gpx4fl/fl mice with Adipoq-Cre+ (Gpx4-/-AT) or Fabp4-Cre+ (Gpx4+/-Fabp4) mice. Both models were metabolically characterized by a glucose tolerance test and insulin resistance test, and adipose tissue lipid peroxidation, inflammation and cell death were assessed by quantifying oxygen-specific epitopes, transcriptional analysis of chemokines, quantification of F4/80+ macrophages and TUNEL labelling. RESULTS: GPX4 expression was induced during and required for adipocyte differentiation. In mature adipocytes, impaired GPX4 activity spontaneously evoked lipid peroxidation and expression of inflammatory cytokines such as TNF-α, interleukin 1ß (IL-1ß), IL-6 and the IL-8 homologue CXCL1. Gpx4-/-AT mice spontaneously displayed adipocyte hypertrophy on a chow diet, which was paralleled by the accumulation of oxygen-specific epitopes and macrophage infiltration in adipose tissue. Furthermore, Gpx4-/-AT mice spontaneously developed glucose intolerance, hepatic insulin resistance and systemic low-grade inflammation, when compared to wildtype littermates, which was similarly recapitulated in Gpx4+/-Fabp4 mice. Gpx4-/-AT mice exhibited no signs of adipocyte death. CONCLUSION: Adipocyte GPX4 protects against spontaneous metabolic dysregulation and systemic low-grade inflammation independent from ferroptosis, which could be therapeutically exploited in the future.


Asunto(s)
Resistencia a la Insulina , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Animales , Citocinas/metabolismo , Dieta Alta en Grasa , Epítopos/metabolismo , Inflamación/metabolismo , Mamíferos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , Oxígeno/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa
15.
Exp Clin Endocrinol Diabetes ; 130(6): 406-414, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34407548

RESUMEN

OBJECTIVE: Laparoscopic adjustable gastric banding (LAGB) was found to be effective in reducing body weight and improving insulin resistance in patients with obesity and non-alcoholic fatty liver disease (NAFLD). The adipokine/myokine meteorin-like (METNRL) is an important regulator of whole-body energy expenditure. Krüppel-like factor 3 (KLF3), a regulator of METRNL expression in eosinophils, inhibits the beiging of adipose tissue in mice and therefore regulates adipose tissue development. METHODS: Thirty-three obese patients undergoing LAGB were included in the study. The hepatic and adipose tissue expression of METNRL and KLF3 was determined before (t0) and 6 months after (t6) LABG. The human liver cancer cell line (HepG2) was stimulated with cytokines and fatty acids and METNRL and KLF3 expressions were analyzed. RESULTS: LAGB-associated weight loss was correlated with decreased hepatic METNRL expression. The expression of METNRL and KLF3 in hepatic-and adipose tissues correlated before and after LAGB. Individuals with augmented LAGB-induced weight loss (>20 kg) showed lower hepatic METNRL and KLF3 expression before and after LAGB than patients with <20 kg weight loss. METNRL and KLF3 levels were higher in patients with higher NAFLD activity scores. HepG2 stimulation with interleukin-1ß, tumor necrosis factor-α, palmitic acid but not interleukin-6, oleic acid, or lipopolysaccharide, induced the expression of one or both investigated adipokines. CONCLUSIONS: The novel description of METRNL and KLF3 as hepatokines could pave the way to target their production and/or signaling in obesity, NAFLD, and related disorders. Both proteins may act as possible biomarkers to estimate weight loss after bariatric surgery.


Asunto(s)
Gastroplastia , Factores de Transcripción de Tipo Kruppel/metabolismo , Laparoscopía , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Adipoquinas , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Obesidad Mórbida/cirugía , Pérdida de Peso/fisiología
16.
Clin Transl Gastroenterol ; 12(1): e00293, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33438988

RESUMEN

INTRODUCTION: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ. METHODS: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls. RESULTS: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values. DISCUSSION: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.


Asunto(s)
COVID-19/complicaciones , Heces/química , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/virología , Neopterin/análisis , Adulto , Anciano , Austria/epidemiología , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/virología , Estudios de Casos y Controles , Femenino , Enfermedades Gastrointestinales/diagnóstico , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/virología , Humanos , Inflamación/inmunología , Inflamación/virología , Pacientes Internos , Interferón gamma/metabolismo , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , SARS-CoV-2/genética
17.
Gut ; 70(3): 585-594, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32699098

RESUMEN

OBJECTIVE: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. DESIGN: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. RESULTS: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. CONCLUSION: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.


Asunto(s)
Hepatopatías Alcohólicas/metabolismo , alfa 1-Antitripsina/fisiología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Genotipo , Humanos , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/mortalidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Infiltración Neutrófila/efectos de los fármacos , Análisis de Supervivencia , alfa 1-Antitripsina/genética
18.
Cytokine ; 133: 155114, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32442908

RESUMEN

Obesity has emerged as a substantial global healthcare issue that is frequently associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD). Tsukushi (TSK), a liver-derived molecule, was recently identified as a major driver of NAFLD. Laparoscopic adjustable gastric banding (LAGB) has proven effective in reducing body weight and improving NAFLD. We therefore aimed to investigate the relation between LAGB-induced weight loss and TSK expression. Twenty-six obese patients undergoing LAGB were included in the study and metabolic parameters were assessed before (t0) and six months after LAGB (t6). The expression of TSK in liver and subcutaneous adipose tissue (AT) specimens was determined at both time points. To unravel regulatory mechanisms of TSK expression, human peripheral blood mononuclear cells (PBMCs) were stimulated with pro-inflammatory cytokines and TSK mRNA levels were analyzed by quantitative polymerase chain reaction. LAGB induced pronounced weight loss which was paralleled by amelioration of metabolic disturbances and histologically defined NAFLD. While hepatic TSK expression was markedly decreased after LAGB, adipose tissue TSK expression remained comparable to baseline. The decline in hepatic TSK expression after LAGB positively correlated with weight loss and the reduction in BMI, and negatively correlated with NAFLD activity score (NAS). In human PBMCs, pro-inflammatory cytokines such as IL-1ß and TNFα induced the expression of TSK. In conclusion, LAGB-induced weight loss reduces hepatic TSK expression. Inhibiting TSK might represent a promising target for treating NAFLD in the future.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Hígado/metabolismo , Proteoglicanos/metabolismo , Pérdida de Peso/fisiología , Adulto , Cirugía Bariátrica/métodos , Células Cultivadas , Citocinas/metabolismo , Femenino , Gastroplastia/métodos , Humanos , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Leucocitos Mononucleares/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Grasa Subcutánea/metabolismo
19.
Liver Int ; 40(7): 1610-1619, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32306456

RESUMEN

BACKGROUND & AIMS: Alcohol-related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl-fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. METHODS: Dimethyl-fumarate or vehicle was orally administered to wild-type mice receiving a Lieber-DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical- and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol-induced intestinal barrier disruption. RESULTS: Dimethyl-fumarate protected against ethanol-induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf-α, Il-1ß, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol-fed and DMF-treated mice when compared to vehicle. DMF protected against ethanol-induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS-induced cytokine responses of KCs. CONCLUSIONS: Dimethyl-fumarate counteracts ethanol-induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.


Asunto(s)
Hígado Graso Alcohólico , Hepatopatías Alcohólicas , Animales , Dimetilfumarato/farmacología , Inflamación/tratamiento farmacológico , Hígado , Hepatopatías Alcohólicas/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL
20.
Nat Commun ; 11(1): 1775, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32286299

RESUMEN

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.


Asunto(s)
Enfermedad de Crohn/metabolismo , Grasas de la Dieta/efectos adversos , Enteritis/metabolismo , Ácidos Grasos Insaturados/metabolismo , Inflamación/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Adulto , Animales , Muerte Celular/genética , Muerte Celular/fisiología , Enfermedad de Crohn/genética , Enteritis/etiología , Enteritis/genética , Ácidos Grasos Insaturados/genética , Femenino , Glutatión Peroxidasa/metabolismo , Humanos , Inflamación/genética , Peroxidación de Lípido/genética , Peroxidación de Lípido/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética
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